U.S. patent application number 12/373584 was filed with the patent office on 2010-03-04 for novel compositions.
Invention is credited to Daniel Raederstorff, Nathalie Richard, Joseph Schwager, Karin Wertz.
Application Number | 20100056463 12/373584 |
Document ID | / |
Family ID | 37591880 |
Filed Date | 2010-03-04 |
United States Patent
Application |
20100056463 |
Kind Code |
A1 |
Raederstorff; Daniel ; et
al. |
March 4, 2010 |
NOVEL COMPOSITIONS
Abstract
The present invention relates to novel compositions comprising
hydroxytyrosol and/or oleuropein (I) and at least one additional
component e.g. selected from the group of ligustilide, oleuropein
aglycone, magnolol, honokiol, genistein, resveratrol, EGCG,
magnolia bark extract, cashew fruit extract and Glycyrrhiza foetida
as well as to the use of these compositions as a medicament, in
particular as a medicament for the treatment, co-treatment or
prevention of inflammatory disorders.
Inventors: |
Raederstorff; Daniel;
(Flaxlanden, FR) ; Richard; Nathalie; (Mulhouse,
FR) ; Schwager; Joseph; (Basel, CH) ; Wertz;
Karin; (Rheinfelden, DE) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
901 NORTH GLEBE ROAD, 11TH FLOOR
ARLINGTON
VA
22203
US
|
Family ID: |
37591880 |
Appl. No.: |
12/373584 |
Filed: |
July 12, 2007 |
PCT Filed: |
July 12, 2007 |
PCT NO: |
PCT/EP2007/006188 |
371 Date: |
November 4, 2009 |
Current U.S.
Class: |
514/23 ;
514/734 |
Current CPC
Class: |
A61P 19/00 20180101;
A61P 35/00 20180101; A61P 11/06 20180101; A61P 43/00 20180101; A61P
9/10 20180101; A61P 17/08 20180101; A61K 31/343 20130101; A61P 9/00
20180101; A61P 17/06 20180101; A61P 29/00 20180101; A61P 17/00
20180101; A61P 17/02 20180101; A61P 37/08 20180101; A61K 31/366
20130101; A61P 19/02 20180101; A61K 31/05 20130101; A61P 25/28
20180101; A61P 1/04 20180101; A61K 31/05 20130101; A61K 2300/00
20130101; A61K 31/343 20130101; A61K 2300/00 20130101; A61K 31/366
20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/23 ;
514/734 |
International
Class: |
A61K 31/7004 20060101
A61K031/7004; A61K 31/05 20060101 A61K031/05 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 14, 2006 |
EP |
06014645.3 |
Claims
1. A composition comprising hydroxytyrosol and/or oleuropein (I)
and at least one additional component selected from the group of
ligustilide, oleuropein aglycone (II), tyrosol, extract from the
bark of Magnolia officinalis, magnolol, honokiol, genistein,
resveratrol, EGCG methylsulfonylmethane, SAMe, collagen
hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein,
zeaxanthin, .beta.-cryptoxanthin, Devil's Claw, milk protein
concentrate, solubilized keratin, celery seed extract, cetylated
fatty acids, carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract.
2. The composition as in claim 1, wherein at least one additional
component is selected from the group of ligustilide, oleuropein
aglycone (II), magnolol, honokiol, genistein, resveratrol, EGCG,
boswellic acid, magnolia bark extract, cashew fruit extract and
Glycyrrhiza foetida.
3. The composition as in claim 1 comprising hydroxytyrosol,
lycopene and resveratrol.
4. The composition as in claim 1, wherein the hydroxytyrosol is in
the form of a hydroxytyrosol containing olive extract.
5. A use of a composition as in claim 1 as an agent for the
treatment, co-treatment or prevention of inflammatory
disorders.
6. A use of a composition in claim 1 for maintenance of joint
health.
7. A use of a composition as in claim 1 as an agent for treatment,
co-treatment and prevention of joint disorders.
8. A nutraceutical comprising a composition as in claim 1 and a
nutraceutically acceptable carrier.
9. The nutraceutical as in claim 8 which is a food product,
foodstuff, dietary supplement, nutritional supplement or a
supplement composition for a food product or a foodstuff.
10. The nutraceutical composition as in claim 8 wherein the amount
of hydroxytyrosol and/or oleuropein (I) is 0.01 to 1 g, more
preferably 0.2 mg to 500 mg per serving.
11. The composition as in claim 1 for use as a medicament.
12. A use of a composition as in claim 1, for the manufacture of a
medicament for the treatment, co-treatment or prevention of
inflammatory disorders.
13. The use as in claim 12, wherein the inflammatory disorder is
arthritis.
14. The use as in claim 12 wherein the inflammatory disorder is an
inflammation of the skin.
15. A pharmaceutical comprising a composition as in claim 1 and a
pharmaceutically acceptable carrier.
16. The pharmaceutical as in claim 15, which is in the form of a
powder, tablet, capsule, gel, liquid or solid.
17. The pharmaceutical as in claim 15, which is for dermatological
purposes.
18. A cosmetic composition comprising a composition as in claim 1
and a cosmetically acceptable carrier.
19. The cosmetic composition as in claim 18 which is a skin care
preparation.
20. A method for treatment, co-treatment or prevention of
inflammatory disorders in animals said method comprising the step
of administering an effective amount of the composition as in claim
1 to an animal, which are in need of such a treatment.
21. The method as in claim 20, wherein the inflammatory disorder is
arthritis.
22. The method as in claim 20, wherein the inflammatory disorder is
an inflammation of the skin.
23. Use of hydroxytyrosol and/or oleuropein (I) for enhancing the
anti-inflammatory activity of one or several compounds selected
from the group of ligustilide, oleuropein aglycone (II), tyrosol,
extract from the bark of Magnolia officinalis, magnolol, honokiol,
genistein, resveratrol, EGCG methylsulfonylmethane, SAMe, collagen
hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein,
zeaxanthin, .beta.-cryptoxanthin, Devil's Claw, milk protein
concentrate, solubilized keratin, celery seed extract, cetylated
fatty acids, carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract.
24. Method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I) which comprises adding to a composition containing
hydroxytyrosol and/or oleuropein (I) an effective amount of one or
several components selected from the group of ligustilide,
oleuropein aglycone (II), tyrosol, extract from the bark of
Magnolia officinalis, magnolol, honokiol, genistein, resveratrol,
EGCG methylsulfonylmethane, SAMe, collagen hydrolysate, collagen,
ascorbyl phosphate, lycopene, lutein, zeaxanthin,
.beta.-cryptoxanthin, Devil's Claw, milk protein concentrate,
solubilized keratin, celery seed extract, cetylated fatty acids,
carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract.
Description
[0001] The present invention relates to novel compositions
comprising hydroxytyrosol and/or oleuropein (I) and at least one
additional component selected from the group of ligustilide,
oleuropein aglycone (II), tyrosol, extract from the bark of
Magnolia officinalis, magnolol, honokiol, genistein, resveratrol,
EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen,
ascorbyl phosphate, lycopene, lutein, zeaxanthin,
.beta.-cryptoxanthin, Devil's Claw, milk protein concentrate,
solubilized keratin, celery seed extract, cetylated fatty acids,
carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract as
well as to the use of these compositions as a medicament, in
particular as a medicament for the treatment, co-treatment or
prevention of inflammatory disorders.
[0002] Inflammatory disorders are one of the most important health
problems in the world. Inflammation is in general a localized
protective response of the body tissues to invasion of the host by
foreign material or injurious stimuli. The causes of inflammation
can be infectious agents such as bacteria, viruses, and parasites;
or physical agents such as burns or radiation; or chemicals like
toxins, drugs or industrial agents; or immunological reactions such
as allergies and autoimmune responses or conditions associated with
oxidative stress.
[0003] Inflammation is characterized by pain, redness, swelling,
heat, and eventual loss of function of the affected area. These
symptoms are the results of a complex series of interactions mainly
taking place between the cells of the immune system. The response
of the cells results in an interacting network of several groups of
inflammatory mediators: Proteins (e.g., cytokines, enzymes [e.g.,
proteases, peroxydase], major basic protein, adhesion molecules
[ICAM, VCAM]), lipid mediators (e.g., eicosanoids, prostaglandins,
leukotrienes, platelet activating factor [PAF]), reactive oxygen
species (e.g., hydroperoxides, superoxyde anion O.sub.2--, nitric
oxide [NO] etc). However, many of those mediators of inflammation
are also regulators of normal cellular activity. Thus, deficiencies
of inflammatory reactions lead to a compromised host (i.e.
infection) while uncontrolled and thus chronic inflammation leads
to inflammatory diseases mediated in part by the excessive
production of several of the above mentioned mediators.
[0004] Acute and chronic inflammation resulting from an excessive
biosynthesis of inflammatory mediators is involved in numerous
inflammatory disorders such as arthritis (e.g. osteoarthritis,
rheumatoid arthritis), asthma, inflammatory bowel diseases,
inflammatory diseases of the skin (e.g. contact dermatitis
[particularly diaper area dermatitis], atopic dermatitis, xerosis,
eczema, rosacea, seborrhea, psoriasis, neurodermitis, thermal and
radiation burns such as sunburn, other types of skin inflammation,
and the tissue-degenerating effects of aging) and chronic
inflammatory disorders, such as atherosclerosis, heart diseases,
metabolic syndrome X, cancer, Alzheimer's disease and pre-stages
thereof such as mild cognitive impairment or photoageing which is
associated with chronic skin inflammation.
[0005] Rheumatoid arthritis is a chronic inflammatory disease of
the joints and is one of many different forms of arthritis. For
example, arthritis includes rheumatoid arthritis,
spondyloarthopathies, gouty arthritis, osteoarthritis, systemic
lupus erythematosus and juvenile arthritis. Like asthma, rheumatoid
arthritis is characterized at the molecular level by chronically
unbalanced expression of cytokines, chemokines, kinins and their
receptors, adhesion molecules and their respective receptors, as
well as inflammatory enzymes.
[0006] Psoriasis is one of the most common skin problems, affecting
1-3% of the human population. Inflammatory bowel disease is a
general term used to describe gastrointestinal tract diseases and
includes disorders such as ulcerative colitis and Crohn's
disease.
[0007] Beside the process of intravascular lipid deposition,
inflammatory reactions of the endothelial (i.e. blood vessel) wall
are considered to critically contribute to atherosclerosis i.e.
atheroma formation. Atherosclerosis results from vascular injury
which triggers inflammation. Activated macrophages, T-lymphocytes,
and eventually smooth muscle cells are present in atherosclerotic
plaques. Monocyte/macrophage and lymphocyte activation leads to the
release of eicosanoids, cytokines and matrix metalloproteinases
(MMPs) which are implicated in endothelial damage, as well as in
the formation and eventually the rupture of atherosclerotic
plaques. Finally, circulating inflammatory markers such as
C-reactive protein (CRP), fibrinogen, and interleukins are
increased or altered in groups at high-risk of coronary artery
diseases (CAD). Several clinical trials indicate that elevated CRP
concentration correlates with increased risk of coronary, and
vascular events. Thus inflammation appears to play an important
role in the initiation and progression of atheroma formation.
[0008] Inflammatory processes are also associated with the
pathophysiology of Alzheimer's disease. There is evidence of
inflammation in the brain of patients with Alzheimer's disease, as
it is characterized by increased levels of cytokines and activated
microglial cells. Thus, inflammation is not only involved in the
classical inflammatory disorders (e.g., arthritis, asthma, bowel
diseases) but is also associated with many chronic inflammatory
disorders (e.g., atherosclerosis, heart diseases, metabolic
syndrome X, cancer, Alzheimer disease).
[0009] Inflammatory events are also associated with the
pathophysiology of different types of cancers (e.g. gastric and
intestinal cancers, melanomas). Increased levels of inflammatory
mediators such as prostaglandins have been found in cancers of
breast, colon, lung and pancreas in humans.
[0010] Currently, two main classes of drugs, the corticosteroid and
the nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat
inflammatory disorders. NSAIDs and corticosteroids provide
essentially symptomatic relief. Use of corticosteroids has declined
due to a growing concern about the serious side effects of
prolonged use.
[0011] NSAIDs are among the most widely used drugs, primarily for
the treatment of pain and inflammatory disorders, in particular for
the treatment of arthritis (i.e. pain relief). Epidemiological
studies have suggested that patients taking NSAIDs have a lower
risk of developing Alzheimer's disease than those not taking
NSAIDs. A protective effect of NSAIDs suggests that the
cyclooxygenases might be involved in the neurodegenerative process.
Epidemiological studies showed a significant reduction in the risk
of colorectal, gastric, esophageal, and breast cancers among people
who take NSAIDs compared with those not taking NSAIDs. In animal
models, NSAIDs significantly reduced tumor development.
[0012] However, long-term use of NSAIDs when treating chronic
diseases such as arthritis, is limited by severe side-effects like
serious gastrointestinal complications, renal toxicity or asthmatic
reactions.
[0013] Therefore, there is a need for new anti-inflammatory agents
with weak or no side effects. Patients with inflammatory diseases
have a special interest in a type of treatment considered as
"natural" with mild anti-inflammatory effects and without major
side effects, which can be used for disease prevention and as
adjuvant treatment. Furthermore, the treatment used needs to
maintain the equilibrium between excessive and insufficient
inflammatory reaction.
[0014] There are many known examples of such "natural" agents with
shown anti-inflammatory action. However, a disadvantage of these
"natural" compounds is that their biological and thus inhibitory
activity is often inadequate. When two or more natural substances
are applied concomitantly, their action can be additively or even
synergistically enhanced. This lowers the required amount of each
substance in order to effect disease development or treatment.
Since lower doses of each of the natural substances individually
can be used, there is less chance that deleterious levels are
reached and also less chance of serious side-effects due to chronic
use.
[0015] The invention relates to a composition comprising
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
and at least one additional component selected from the group of
ligustilide, oleuropein aglycone (II), tyrosol, extract from the
bark of Magnolia officinalis, magnolol, honokiol, genistein,
resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen
hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein,
zeaxanthin, .beta.-cryptoxanthin, Devil's Claw, milk protein
concentrate, solubilized keratin, celery seed extract, cetylated
fatty acids, carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract.
Preferably, the invention relates to a composition comprising
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
and at least one additional component selected from the group of
ligustilide, oleuropein aglycone, magnolol, honokiol, genistein,
resveratrol, EGCG, magnolia bark extract, cashew fruit extract and
Glycyrrhiza foetida. Even more preferably, the invention relates to
a composition comprising hydroxytyrosol and/or oleuropein (I), in
particular hydroxytyrosol, and at least one additional component
selected from the group of ligustilide, magnolol, genistein,
resveratrol, EGCG, magnolia bark extract, cashew fruit extract and
Glycyrrhiza foetida. In a most preferred embodiment, the invention
relates to a composition comprising hydroxytyrosol and/or
oleuropein (I), in particular hydroxytyrosol, and at least one
additional component selected from the group of ligustilide,
honokiol, genistein, resveratrol and EGCG.
[0016] Thus in one preferred embodiment the invention relates to a
composition comprising hydroxytyrosol and/or oleuropein (I) and
ligustilide, most preferably to a composition comprising
hydroxytyrosol and ligustilide or a composition comprising
oleuropein and ligustilide.
[0017] In another preferred embodiment the invention relates to a
composition comprising hydroxytyrosol and/or oleuropein (I) and
honokiol, most preferably to a composition comprising
hydroxytyrosol and honokiol. Most preferably, honokiol is used in
the form of an extract from the bark of Magnolia officinalis
comprising honokiol and magnolol.
[0018] In a further preferred embodiment the invention relates to a
composition comprising hydroxytyrosol and/or oleuropein (I) and
genistein, most preferably to a composition comprising
hydroxytyrosol and genistein.
[0019] In an additional preferred embodiment the invention relates
to a composition comprising hydroxytyrosol and/or oleuropein (I)
and resveratrol, most preferably to a composition comprising
hydroxytyrosol and resveratrol or a composition comprising
oleuropein and resveratrol.
[0020] In a further preferred embodiment the invention relates to a
composition comprising hydroxytyrosol and/or oleuropein (I) and
EGCG, most preferably to a composition comprising hydroxytyrosol
and EGCG.
[0021] In all of the above mentioned embodiments preferably the
molar ratio of hydroxy-tyrosol, respectively oleuropein to the
additional ingredient is about 1 to 1.
[0022] In another preferred embodiment the invention relates to a
composition comprising hydroxytyrosol and/or oleuropein (I), in
particular hydroxytyrosol, and lycopene and resveratrol. Particular
preferred are compositions wherein the molar ratio of lycopene is
smaller than the molar amount of resveratrol and of hydroxytyrosol
and the molar amount of resveratrol and hydroxytyrosol is equal.
Most preferably, the molar ratio of lycopene to resveratrol to
hydroxytyrosol is in the range of about 1:2:2 to 1:10:10, in
particular 1:4:4 to 1:8:8, most in particular in the range of
1:6:6.
[0023] It has surprisingly been found that the individual
components in the composition of the present invention function
synergistically in their anti-inflammatory activity. Moreover, the
composition of the present invention may be especially useful in
the treatment, co-treatment and prevention of inflammatory
disorders, such as heart disease, multiple sclerosis, osteo- and
rheumatoid arthritis, atherosclerosis, and osteoporosis.
[0024] The composition of the present invention is especially
suitable for the treatment, co-treatment and prevention of
different forms of arthritis, in particular osteoarthritis and
rheumatoid arthritis. Also, the composition of the present
invention is suitable as an agent for treatment, co-treatment and
prevention of joint disorders in particular for reduction of joint
inflammation, maintenance and/or increase of joint health,
prevention of joint stiffness, increase of joint mobility,
providing supple and/or flexible joints, lubrication of the joints,
relief of pain associated with joint inflammation, decrease of
joint swelling, lessening joint problems, and providing joint care.
Thus, the invention also relates to the use of a composition of the
invention as an agent for the treatment, co-treatment or prevention
of inflammatory disorders as well as joint disorders.
[0025] In a different aspect, the invention also relates to the
composition of the invention for use as a medicament.
[0026] In yet another embodiment, the invention relates to the use
of a composition according to the invention for the manufacture of
a nutraceutical, pharmaceutical, cosmetic or dermatological
preparation suitable for the treatment, co-treatment or prevention
of inflammatory disorders, more preferably of arthritis or skin
inflammation, most preferably of osteoarthritis or sunburn.
[0027] Also, the invention relates to a method for treatment,
co-treatment and prevention of inflammatory disorders, in
particular of arthritis, more in particular of osteoarthritis or
rheumatoid arthritis, in animals including humans said method
comprising the step of administering `an effective amount of the
composition according to the invention` to animals including
humans, which are in need thereof. Preferably, the inflammatory
disorder is arthritis, most preferably osteoarthritis.
[0028] The term `an effective amount of the composition according
to the invention` refers to an amount necessary to obtain a
physiological effect. The physiological effect may be achieved by
one single dose or by repeated doses. The dosage administered may,
of course, vary depending upon known factors, such as the
physiological characteristics of the particular composition and its
mode and route of administration; the age, health and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; and the effect
desired and can be adjusted by a person skilled in the art.
[0029] In the framework of the invention, with animals is meant all
animals, including mammals, examples of which include humans.
Preferred examples of mammals beside humans are non-ruminant or
ruminant animals including cats, dogs, dromedaries, camels,
elephants, and horses.
[0030] In another embodiment the invention relates to a
nutraceutical composition comprising the composition according to
the invention and a nutraceutically acceptable carrier.
[0031] The term nutraceutical composition as used herein include
food product, foodstuff, dietary supplement, nutritional supplement
or a supplement composition for a food product or a foodstuff.
[0032] Thus, in another embodiment the present invention relates to
a nutraceutical wherein the nutraceutical is a food product,
foodstuff, dietary supplement, nutritional supplement or a
supplement composition for a food product or a foodstuff.
[0033] As used herein, the term food product refers to any food or
feed suitable for consumption by humans or animals. The food
product may be a prepared and packaged food (e.g., mayonnaise,
salad dressing, bread, or cheese food) or an animal feed (e.g.,
extruded and pelleted animal feed, coarse mixed feed or pet food
composition). As used herein, the term foodstuff refers to any
substance fit for human or animal consumption. The term dietary
supplement refers to a small amount of a compound for
supplementation of a human or animal diet packaged in single or
multiple dose units. Dietary supplements do not generally provide
significant amounts of calories but may contain other
micronutrients (e.g., vitamins or minerals). The term nutritional
supplement refers to a composition comprising a dietary supplement
in combination with a source of calories. In some embodiments,
nutritional supplements are meal replacements or supplements (e.g.,
nutrient or energy bars or nutrient beverages or concentrates).
[0034] Food products or foodstuffs are for example beverages such
as non-alcoholic and alcoholic drinks as well as liquid preparation
to be added to drinking water and liquid food, non-alcoholic drinks
are for instance soft drinks, sport drinks, fruit juices, such as
for example orange juice, apple juice and grapefruit juice;
lemonades, teas, near-water drinks and milk and other dairy drinks
such as for example yoghurt drinks, and diet drinks. In another
embodiment food products or foodstuffs refer to solid or semi-solid
foods comprising the composition according to the invention. These
forms can include, but are not limited to baked goods such as cakes
and cookies, puddings, dairy products, confections, snack foods, or
frozen confections or novelties (e.g., ice cream, milk shakes),
prepared frozen meals, candy, snack products (e.g., chips), liquid
food such as soups, spreads, sauces, salad dressings, prepared meat
products, cheese, yogurt and any other fat or oil containing foods,
and food ingredients (e.g., wheat flour).
[0035] The term food products or foodstuffs also includes
functional foods and prepared food products, the latter referring
to any pre-packaged food approved for human consumption.
[0036] Animal feed including pet food compositions advantageously
include food intended to supply necessary dietary requirements, as
well as treats (e.g., dog biscuits) or other food supplements. The
animal feed comprising the composition according to the invention
may be in the form of a dry composition (for example, kibble),
semi-moist composition, wet composition, or any mixture thereof.
Alternatively or additionally, the animal feed is a supplement,
such as a gravy, drinking water, yogurt, powder, suspension, chew,
treat (e.g., biscuits) or any other delivery form.
[0037] Dietary supplements of the present invention may be
delivered in any suitable format. In preferred embodiments, dietary
supplements are formulated for oral delivery. The ingredients of
the dietary supplement of this invention are contained in
acceptable excipients and/or carriers for oral consumption. The
actual form of the carrier, and thus, the dietary supplement
itself, is not critical. The carrier may be a liquid, gel, gelcap,
capsule, powder, solid tablet (coated or non-coated), tea, or the
like. The dietary supplement is preferably in the form of a tablet
or capsule and most preferably in the form of a hard (shell)
gelatin capsule. Suitable excipient and/or carriers include
maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium
phosphate, microcrystalline cellulose, dextrose, rice flour,
magnesium stearate, stearic acid, croscarmellose sodium, sodium
starch glycolate, crospovidone, sucrose, vegetable gums, lactose,
methylcellulose, povidone, carboxymethylcellulose, corn starch, and
the like (including mixtures thereof). Preferred carriers include
calcium carbonate, magnesium stearate, maltodextrin, and mixtures
thereof. The various ingredients and the excipient and/or carrier
are mixed and formed into the desired form using conventional
techniques. The tablet or capsule of the present invention may be
coated with an enteric coating that dissolves at a pH of about 6.0
to 7.0. A suitable enteric coating that dissolves in the small
intestine but not in the stomach is cellulose acetate phthalate.
Further details on techniques for formulation for and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0038] In other embodiments, the dietary supplement is provided as
a powder or liquid suitable for adding by the consumer to a food or
beverage. For example, in some embodiments, the dietary supplement
can be administered to an individual in the form of a powder, for
instance to be used by mixing into a beverage, or by stirring into
a semi-solid food such as a pudding, topping, sauce, puree, cooked
cereal, or salad dressing, for instance, or by otherwise adding to
a food e.g. enclosed in caps of food or beverage container for
release immediately before consumption. The dietary supplement may
comprise one or more inert ingredients, especially if it is
desirable to limit the number of calories added to the diet by the
dietary supplement. For example, the dietary supplement of the
present invention may also contain optional ingredients including,
for example, herbs, vitamins, minerals, enhancers, colorants,
sweeteners, flavorants, inert ingredients, and the like.
[0039] In some embodiments, the dietary supplements further
comprise vitamins and minerals including, but not limited to,
calcium phosphate or acetate, tribasic; potassium phosphate,
dibasic; magnesium sulfate or oxide; salt (sodium chloride);
potassium chloride or acetate; ascorbic acid; ferric
orthophosphate; niacinamide; zinc sulfate or oxide; calcium
pantothenate; copper gluconate; riboflavin; beta-carotene;
pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin;
chromium chloride or picolonate; potassium iodide; sodium selenate;
sodium molybdate; phylloquinone; vitamin D3; cyanocobalamin; sodium
selenite; copper sulfate; vitamin A; vitamin C; inositol; potassium
iodide. Suitable dosages for vitamins and minerals may be obtained,
for example, by consulting the U.S. RDA guidelines.
[0040] In other embodiments, the present invention provides
nutritional supplements (e.g., energy bars or meal replacement bars
or beverages) comprising the composition according to the
invention. The nutritional supplement may serve as meal or snack
replacement and generally provide nutrient calories. Preferably,
the nutritional supplements provide carbohydrates, proteins, and
fats in balanced amounts. The nutritional supplement can further
comprise carbohydrate, simple, medium chain length, or
polysaccharides, or a combination thereof. A simple sugar can be
chosen for desirable organoleptic properties. Uncooked cornstarch
is one example of a complex carbohydrate. If it is desired that it
should maintain its high molecular weight structure, it should be
included only in food formulations or portions thereof which are
not cooked or heat processed since the heat will break down the
complex carbohydrate into simple carbohydrates, wherein simple
carbohydrates are mono- or disaccharides. The nutritional
supplement contains, in one embodiment, combinations of sources of
carbohydrate of three levels of chain length (simple, medium and
complex; e.g., sucrose, maltodextrins, and uncooked
cornstarch).
[0041] Sources of protein to be incorporated into the nutritional
supplement of the invention can be any suitable protein utilized in
nutritional formulations and can include whey protein, whey protein
concentrate, whey powder, egg, soy flour, soy milk soy protein, soy
protein isolate, caseinate (e.g., sodium caseinate, sodium calcium
caseinate, calcium caseinate, potassium caseinate), animal and
vegetable protein and hydrolysates or mixtures thereof. When
choosing a protein source, the biological value of the protein
should be considered first, with the highest biological values
being found in caseinate, whey, lactalbumin, egg albumin and whole
egg proteins. In a preferred embodiment, the protein is a
combination of whey protein concentrate and calcium caseinate.
These proteins have high biological value; that is, they have a
high proportion of the essential amino acids. See Modern Nutrition
in Health and Disease, eighth edition, Lea & Febiger,
publishers, 1986, especially Volume 1, pages 30-32. The nutritional
supplement can also contain other ingredients, such as one or a
combination of other vitamins, minerals, antioxidants, fiber and
other dietary supplements (e.g., protein, amino acids, choline,
lecithin). Selection of one or several of these ingredients is a
matter of formulation, design, consumer preference and end-user.
The amounts of these ingredients added to the dietary supplements
of this invention are readily known to the skilled artisan.
Guidance to such amounts can be provided by the U.S. RDA doses for
children and adults. Further vitamins and minerals that can be
added include, but are not limited to, calcium phosphate or
acetate, tribasic; potassium phosphate, dibasic; magnesium sulfate
or oxide; salt (sodium chloride); potassium chloride or acetate;
ascorbic acid; ferric orthophosphate; niacinamide; zinc sulfate or
oxide; calcium pantothenate; copper gluconate; riboflavin;
beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic
acid; biotin; chromium chloride or picolonate; potassium iodide;
sodium selenate; sodium molybdate; phylloquinone; vitamin D3;
cyanocobalamin; sodium selenite; copper sulfate; vitamin A; vitamin
C; inositol; potassium iodide.
[0042] The nutritional supplement can be provided in a variety of
forms, and by a variety of production methods. In a preferred
embodiment, to manufacture a food bar, the liquid ingredients are
cooked; the dry ingredients are added with the liquid ingredients
in a mixer and mixed until the dough phase is reached; the dough is
put into an extruder, and extruded; the extruded dough is cut into
appropriate lengths; and the product is cooled. The bars may
contain other nutrients and fillers to enhance taste, in addition
to the ingredients specifically listed herein.
[0043] It is understood by those of skill in the art that other
ingredients can be added to those described herein, for example,
fillers, emulsifiers, preservatives, etc. for the processing or
manufacture of a nutritional supplement.
[0044] Additionally, flavors, coloring agents, spices, nuts and the
like may be incorporated into the nutraceutical composition.
Flavorings can be in the form of flavored extracts, volatile oils,
chocolate flavorings, peanut butter flavoring, cookie crumbs, crisp
rice, vanilla or any commercially available flavoring. Examples of
useful flavoring include, but are not limited to, pure anise
extract, imitation banana extract, imitation cherry extract,
chocolate extract, pure lemon extract, pure orange extract, pure
peppermint extract, imitation pineapple extract, imitation rum
extract, imitation strawberry extract, or pure vanilla extract; or
volatile oils, such as balm oil, bay oil, bergamot oil, cedarwood
oil, walnut oil, cherry oil, cinnamon oil, clove oil, or peppermint
oil; peanut butter, chocolate flavoring, vanilla cookie crumb,
butterscotch or toffee. In one embodiment, the dietary supplement
contains cocoa or chocolate.
[0045] Emulsifiers may be added for stability of the nutraceutical
compositions. Examples of suitable emulsifiers include, but are not
limited to, lecithin (e.g., from egg or soy), and/or mono- and
di-glycerides. Other emulsifiers are readily apparent to the
skilled artisan and selection of suitable emulsifier(s) will
depend, in part, upon the formulation and final product.
Preservatives may also be added to the nutritional supplement to
extend product shelf life. Preferably, preservatives such as
potassium sorbate, sodium sorbate, potassium benzoate, sodium
benzoate or calcium disodium EDTA are used.
[0046] In addition to the carbohydrates described above, the
nutraceutical composition can contain natural or artificial
(preferably low calorie) sweeteners, e.g., saccharides, cyclamates,
aspartamine, aspartame, acesulfame K, and/or sorbitol. Such
artificial sweeteners can be desirable if the nutritional
supplement is intended to be consumed by an overweight or obese
individual, or an individual with type II diabetes who is prone to
hyperglycemia.
[0047] Moreover, a multi-vitamin and mineral supplement may be
added to the nutraceutical compositions of the present invention to
obtain an adequate amount of an essential nutrient, which is
missing in some diets. The multi-vitamin and mineral supplement may
also be useful for disease prevention and protection against
nutritional losses and deficiencies due to lifestyle patterns.
[0048] The dosage and ratios of hydroxytyrosol and/or oleuropein
(I) and the at least one additional component administered via a
nutraceutical will, of course, vary depending upon known factors,
such as the physiological characteristics of the particular
composition and its mode and route of administration; the age,
health and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of
treatment; and the effect desired which can be determined by the
expert in the field with normal trials, or with the usual
considerations regarding the formulation of a nutraceutical
composition.
[0049] In a preferred embodiment, the nutraceutical comprises per
serving an amount of 0.01 to 1 g, more preferably 0.2 mg to 500 mg
of hydroxytyrosol and/or oleuropein (I) and at least one component
selected from [0050] Ligustilide: 0.5 to 500 mg and/or [0051]
Honokiol and/or Magnolol: 0.2 mg to 500 mg of each, preferably in
the form of a magnolia bark extract and/or [0052] Genistein: 0.5 to
500 mg and/or [0053] Resveratrol: 0.2-500 mg, and/or [0054] EGCG:
2.0 to 500 mg and/or [0055] Cardol diene (XII) and/or cardol triene
(XIII): 0.2 to 1000 mg of each, preferably in the form of a cashew
fruit extract (Anacardium occidentale) and/or [0056] Glycyrrhiza
foetida or one or several compounds selected from formula (III) to
(XI): 0.5-1000 mg of each, preferably in the form of a Glycyrrhiza
foetida extract in the indicated amounts.
[0057] In another aspect, the invention relates to a pharmaceutical
comprising the composition according to the invention and a
pharmaceutically acceptable carrier.
[0058] A person skilled in the art knows which carriers can be used
as pharmaceutically acceptable carriers. Suitable pharmaceutical
carriers are e.g. described in Remington's Pharmaceutical Sciences,
supra, a standard reference text in this field. Examples of such
pharmaceutically acceptable carriers are both inorganic and organic
carrier materials, suitable for oral/parenteral/injectable
administration and include water, gelatin, gum arabic, lactose,
starch, magnesium stearate, talc, vegetable oils, and the like.
[0059] The pharmaceutical composition may further comprise
conventional pharmaceutical additives and adjuvants, excipients or
diluents, including, but not limited to, water, gelatin of any
origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum
arabic, vegetable oils, polyalkylene glycols, flavoring agents,
preservatives, stabilizers, emulsifying agents, buffers,
lubricants, colorants, wetting agents, fillers, and the like.
[0060] In a preferred embodiment the pharmaceutical is in the form
of a powder, tablet, capsule, gel, liquid or solid embodiment.
[0061] The dosages and ratios of the individual components in a
pharmaceutical composition can be determined by the expert in the
field with normal preclinical and clinical trials, or with the
usual considerations regarding the formulation of pharmaceutical
composition.
[0062] In a preferred embodiment hydroxytyrosol and/or oleuropein
(I) is administered via a pharmaceutical composition either in the
form of a single dose or by multiple doses in an amount of at least
0.3 mg/kg bodyweight/day, preferably in an amount of 1-450 mg/kg
body weight/day, most preferably in an amount of 4-140 mg/kg body
weight/day.
[0063] The nutraceutical and pharmaceutical according to the
present invention may be in any galenic form that is suitable for
administering to the animal body including the human body, more in
particular in any form that is conventional for oral
administration, e.g. in solid form, for example as
(additives/supplements for) food or feed, food or feed premixes,
fortified food or feed, tablets, pills, granules, dragees,
capsules, and effervescent formulations such as powders and
tablets, or in liquid form, for instance in the form of solutions,
emulsions or suspensions, for example as beverages, pastes and oily
suspensions. The pastes may be filled into hard or soft shell
capsules. Examples for other application forms are forms for
transdermal, parenteral, topical or injectable administration. The
nutraceutical and pharmaceutical may be in the form of controlled
(delayed) release formulation. Examples of pharmaceuticals also
include compositions suitable for topical application such as
cremes, gels, sprays, dry sticks, powders etc.
[0064] The term hydroxytyrosol relates to `pure hydroxytyrosol` of
either synthetic origin or obtainable from natural sources such as
from products and by-products derived from the olive tree by
extraction and/or purification. Additionally the term
hydroxytyrosol encompasses hydroxytyrosol comprising extracts
obtainable e.g. from products and by-products derived from the
olive tree.
[0065] Products and by products of olive trees encompass olives,
olive tree leafs, olive pulps, olive oil, olive-derived vegetation
water and olive oil dregs without being limited thereto. Based on
the extraction procedure the amount, respectively the ratio of the
hydroxytyrosol can be easily adjusted by a person skilled in the
art. Preferably, hydroxytyrosol is derived from olives that may be
obtained from conventional and commercially available sources such
as growers.
[0066] In case of synthetic or purified hydroxytyrosol, the term
`pure hydroxytyrosol` relates to hydroxytyrosol having a purity of
at least 90%, more preferably a purity of at least 91%, even more
preferably a purity of at least 92%, even more preferably a purity
of at least 93%, even more preferably a purity of at least 94%,
even more in particular a purity of at least 95%, in particular a
purity of at least 96%, more in particular a purity of at least
97%, even more in particular a purity of at least 98%, most in
particular a purity of at least 99%. The purity of hydroxytyrosol
can be determined by methods known to a person skilled in the art
such as e.g. by HPLC, or LC-MS.
[0067] The hydroxytyrosol employed herein can be prepared by a
number of methods known in the art. The olives may be processed by
any suitable means to obtain the compositions described. For
example, the olives and/or olive leaves may be pressed to obtain a
mixture including olive oil, vegetation water and solid byproducts.
The hydroxytyrosol may be obtained directly from the mixture or the
mixture may be fractionated and/or purified to obtain the
hydroxytyrosol. The compositions may be fractionated and/or
purified by a number of methods known to the person skilled in the
art. Examples of fractionating methods include partitioning with an
organic solvent, chromatography, for example high pressure liquid
chromatography (HPLC) or the use of supercritical fluids.
[0068] Examples of references that deal with the extraction of
hydroxytyrosol from olive leaves are WO02/18310 A1, US 2002/0198415
A1, WO2004/005228 A1, U.S. Pat. No. 6,416,808 and US 2002/0058078
A1 which disclose a method for acidic hydrolysis of olive
vegetation water for 2 to 12 months until at least 90% of the
present oleuropein has been converted. A method of extraction of
hydroxytyrosol from olives, olive pulps, olive oil and oil mill
waste water is described by Usana Inc. U.S. Pat. No. 6,361,803 and
WO01/45514 A1 and in US 2002/0004077 A1. EP 1 582 512 A1 describes
an extraction of hydroxytyrosol from olive leaves. A method for
obtaining hydroxytyrosol from the vegetation water of de-pitted
olives is disclosed in US 2004/0039066 A1 in paragraphs
[0080]-[0091].
[0069] Commercially available hydroxytyrosol containing olive
extracts which may be used according to the invention include e.g.
extracts from olive fruits such as Polyphen-Oil.TM. from Life
Extension, OleaSelect.TM. from Indena, Hytolive.RTM. from Genosa,
Prolivols from Seppic, OLIVE LEAF or OLIVE Water Extract of Olea
europea from Lalilab, Hitofulvic and Olife.TM. from Ebiser,
hydrolysed olive leaf extract, such as described in EP1582512,
olive leaf extract, rich in oleuropein, such as available from
Furfural and HIDROX.RTM. from CreAgri.
[0070] Preferably HIDROX.RTM. from CreAgri such as HIDROXO.RTM. 2%
spray dried powder, HIDROX.RTM. Gold freeze dried powder (9%) and
HIDROX.RTM. 6% freeze dried powder organic olive juice extract are
used.
[0071] An example of a synthetic process in which hydroxytyrosol
may be prepared with a purity >90% is a process comprising the
steps of hydrogenating 3,4-dihydroxymandelic acid or a
3,4-dihydroxymandelic acid C.sub.1-10-alkyl ester in a
C.sub.1-10-alkanol in the presence of a precious metal
hydrogenation catalyst and optional reduction of the formed
(3,4-dihydroxyphenyl)-acetic acid C.sub.1-10-alkyl ester is to form
2-(3,4-dihydroxyphenyl)-ethanol (=hydroxytyrosol) a specific
example of which is described below.
[0072] The hydrogenation may be carried out in the presence of a
precious metal catalyst such as Pd and Rh, separately or in
mixtures, in a manner known per se. In order to increase the
activity and stability of the catalysts they are preferably used on
carriers such as activated carbon, alumina or kieselguhr. The
preferred hydrogenation catalyst in the present case is Pd/C.
[0073] The hydrogenation is carried out in the presence of a lower
alkanol, i.e. a C.sub.1-10-alkanol, such as methanol, ethanol,
propanol, isopropanol, butanol, preferably in methanol or ethanol,
preferably in the presence of a strong acid, preferably
hydrochloric acid, preferably at a temperature from ambient
temperature to 100.degree. C. or higher, preferably from
40-65.degree. C., preferably at a hydrogen pressure at least higher
than the vapor pressure of the solvent at the hydrogenation
temperature. The pressure can be from normal, i.e. atmospheric
pressure, to 100 bar or higher.
[0074] If desired, the reaction which is preferably carried out as
a through process can be accomplished in two separate steps, i.e.,
a first step wherein an ester of 3,4-dihydroxymandelic acid is
built by esterification of the acid and a second step wherein the
3,4-dihydroxymandelic acid lower alkyl ester is hydrogenated. The
reduction of the (3,4-dihydroxyphenyl)-acetic acid C.sub.1-10-alkyl
ester to give hydroxytyrosol can be achieved in a known manner. The
preferred reduction agents are complex hydrids of aluminum and
boron, such as LiAlH.sub.4 and NaBH.sub.4. The starting material,
3,4-dihydroxymandelic acid, is well-known and can be prepared in
accordance with methods described in the literature, e.g., by
condensation of catechol with glyoxylic acid.
[0075] Preferably hydroxytyrosol is used in the form of a
hydroxytyrosol containing olive extract.
[0076] Hydroxytyrosol is used in an amount of sufficient to
administer to animals including humans (e.g. weighing about 70 kg)
a dosage of at least 0.02 mg/day. Preferably hydroxytyrosol is used
in a concentration so that the daily consumption by an animal
including humans (e.g. weighing about 70 kg) is in the range of
from 1 mg/day to 2000 mg/day, more preferably from 5 mg/day to 500
mg/day. Thus, the daily dosage is at least about 0.3 .mu.g/kg body
weight, preferably an average dosage of 0.01-30 mg/kg body weight,
most preferable of 0.1-10 mg/kg of bodyweight is used.
[0077] A nutraceutical composition preferably comprises 0.2 mg to
500 mg of hydroxytyrosol per serving, preferably 1 mg to 250 mg. If
the composition is a pharmaceutical composition such composition
may for example comprise hydroxytyrosol in an amount from 1 mg to
500 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg
per daily dose to 500 mg per daily dose of a liquid
formulation.
[0078] If instead of `pure hydroxytyrosol` a hydroxytyrosol
comprising extract is used, the amount of the extract to be used
may be derived from the concentration of `pure hydroxytyrosol`
within the extract and the finding of the optimal dosage is a
matter of routine experimentation for the person skilled in the
art.
[0079] The phenolic compounds oleuropein (I), oleuropein aglycone
(II) and/or tyrosol may either be of synthetic origin or may be
obtained from natural sources such as from products and by-products
derived from the olive tree by extraction and/or purification.
Products and by products of olive trees encompass olives, olive
tree leafs, olive pulps, olive oil, olive-derived vegetation water
and olive oil dregs without being limited
[0080] The phenolic compounds oleuropein (I), oleuropein aglycone
(II) or tyrosol employed herein can be prepared by a number of
methods known in the art. E.g. the compounds may be derived from
olives which may be processed by any suitable means to obtain the
compounds described. For example, the olives and/or olive leaves
may be pressed to obtain a mixture including olive oil, vegetation
water and solid byproducts. The phenolic compounds may be obtained
directly from the mixture or the mixture may be fractionated and/or
purified to obtain the phenolic compounds. The compositions may be
fractionated and/or purified by a number of methods known to the
person skilled in the art. Examples of fractionating methods
include partitioning with an organic solvent, chromatography, for
example high pressure liquid chromatography (HPLC) or the use of
supercritical fluids.
[0081] The phenolic compounds oleuropein (I), oleuropein aglycone
(II) or tyrosol or mixtures thereof are preferably used in a
concentration so that the daily consumption by an animal including
humans (e.g. weighing about 70 kg) is in the range of from 1 mg/day
to 2000 mg/day, more preferably from 5 mg/day to 500 mg/day. A
nutraceutical composition preferably comprises 0.2 mg to 500 mg of
phenolic compound per serving. If the composition is a
pharmaceutical composition such composition may for example
comprise a phenolic compound in an amount from 1 mg to 2000 mg per
dosage unit, e.g., per capsule or tablet, or from 1 mg per daily
dose to 3000 mg per daily dose of a liquid formulation.
[0082] Ligustilide may be isolated by methods known in the art
[see, e.g., Beck J. J. and Stermitz F. R., J. Natural Products,
Vol. 58, No. 7, pp. 1047-1055, 1995] from various plants such as
Angelica glauca, Angelica acutiloba, Angelica sinensis, Angelicae
dahuricae, Ligusticum acutilobum, Ligusticum officinale, Ligusticum
sinense, Ligusticum wallichii, Cnidium officinale, Rhizoma
Chuanxiong, Pleurospermum hookeri, Trachyspermum roxburghianum,
Meum athamanticum, Lomatium torreyi, Scutellaria baicalensis,
Opopanax chironium, Cenolophium denudatum, Coriandrum sativuum,
Silaum silaus, but may also be synthesized by methods known in the
art. Preferably ligustilide is used in form of a purified plant
extract, e.g., from Ligusticum species, especially L. wallichii,
comprising at least 50 wt.-% of ligustilide, and no more than 10
wt.-% of fatty acids and triglycerides as obtainable by the process
disclosed in European patent application No. 05 002333.2, the
contents of which are incorporated herein by reference.
[0083] Preferably ligustilide is used in an effective dose of 0.01
to 50 mg/kg body weight/day, more preferably 0.1 to 5 mg/kg body
weight/day.
[0084] A nutraceutical preferably comprises 0.5 mg to 500 mg of
ligustilide per serving. If the composition is a pharmaceutical,
such composition may preferably comprise ligustilide in an amount
from 1 mg to 500 mg per dosage unit, e.g., per capsule or tablet,
or from 1 mg per daily dose to 2000 mg per daily dose of a liquid
formulation.
[0085] The term "magnolol" as used herein comprises the pure
compound also known as 5,5'-Diallyl-2,2'-biphenyldiol or
5,5'-di-2-propenyl-[1,1'-Biphenyl]-2,2'-diol (CAS [528-43-8]) and
plant extracts containing the same. The term magnolol also
comprises etherified or esterified hydroxy derivatives from
5,5'-Diallyl-2,2'-biphenyldiol or
5,5'-di-2-propenyl-[1,1'-Biphenyl]-2,2'-diol. The ester or ether
groups may for example be derived from straight or branched alkyl
groups having 1 to 26 carbon atoms or from substituted or
unsubstituted straight or branched aliphatic, araliphatic or
aromatic carboxylic acids having 1 to 26 carbon atoms. Examples of
etherified hydroxy groups further include glycoside groups.
Examples of esterified hydroxy group further include glucuronide or
sulfate groups. Preferably magnolol as used herein is
5,5'-Diallyl-2,2'-biphenyldiol or
5,5'-di-2-propenyl-[1,1'-Biphenyl]-2,2'-diol.
[0086] Plant extracts containing the compound include extracts from
Magnolia officinalis, Magnolia obovata, Magnolia rostrata, Magnolia
bilboa, Magnolia biondii, Magnolia quinquepeta, Magnolia sprengeri,
Manglietia insignis, Manglietia szechuanica, Manglietia
yuyuanensis, Cercidiphyllum japonicum and others. Magnolol is a
known anti-inflammatory agent and is preferably used in the form of
an extract from the bark of Magnolia officinalis, but may of course
also be used in pure form.
[0087] Magnolol is preferably used in a concentration so that the
daily consumption by an animal including humans (e.g. weighing
about 70 kg) is in the range of from 1 mg/day to 2000 mg/day,
preferably from 5 mg/day to 500 mg/day. A nutraceutical preferably
comprises 0.2 mg to 500 mg of magnolol per serving. A
pharmaceutical may for example comprise magnolol in an amount from
1 mg to 500 mg per dosage unit, e.g. per capsule or tablet, of from
5 mg daily dose to 2000 mg per daily dose of a liquid
formulation.
[0088] The term "honokiol" as used herein comprises the pure
compound also known as 3',5-Diallyl-2,4'-biphenyldiol or
3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol (CAS [35354-74-6]) and
plant extracts containing the same.
[0089] The term honokiol also comprises etherified or esterified
hydroxy derivatives from 3',5-Diallyl-2,4'-biphenyldiol or
3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol. The ester or ether
groups may for example be derived from straight or branched alkyl
groups having 1 to 26 carbon atoms or from substituted or
unsubstituted straight or branched aliphatic, araliphatic or
aromatic carboxylic acids having 1 to 26 carbon atoms. Examples of
etherified hydroxy groups further include glycoside groups.
Examples of esterified hydroxy group further include glucuronide or
sulfate groups. Preferably, "honokiol" as used herein is
3',5-Diallyl-2,4'-biphenyldiol or
3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol.
[0090] Plant extracts containing the compound include extracts from
Magnolia officinalis, Magnolia obovata, Magnolia rostrata, Magnolia
bilboa, Magnolia biondii, Magnolia quinquepeta, Magnolia sprengeri,
Manglietia insignis, Manglietia szechuanica, Manglietia
yuyuanensis, Cercidiphyllum japonicum, Machilus thunbergii and
others. Honokiol is a known anti-inflammatory agent and is
preferably used in the form of an extract from the bark of Magnolia
officinalis, buy may of course also be used in pure form.
[0091] Honokiol is preferably use in a concentration so that the
daily consumption by an animal including humans (e.g. weighing
about 70 kg) is in the range of from 1 mg/day to 2000 mg/day,
preferably from 5 mg/day to 500 mg/day. A nutraceutical preferably
comprises 0.2 mg to 500 mg of honokiol per serving. A
pharmaceutical may for example comprise honokiol in an amount from
1 mg to 500 mg per dosage unit, for example per capsule or table,
or from 5 mg per daily dose to about 2000 mg per daily dose of a
liquid formulation.
[0092] Magnolia bark (optionally in dried or ground form) may be
extracted conventionally with solvents like ethanol,
dichloromethane at reflux temperature or at lower temperature.
Alternatively, it may be extracted with supercritical fluids like
SF carbondioxyde or by steam distillation of the bark with water
followed by sampling of the distilled organic part. Sampling may
for example be done by extraction with an organic solvent like
dichloromethane. Subsequent removal of the solvent gives the
desired magnolia bark extract. Optionally the thus obtained
magnolia bark extract may be subjected to further processing steps
to enrich the content of magnolol and/or honokiol to give an
extract of magnolia bark enriched in magnolol and/or honokiol.
[0093] Most preferably in all embodiments of the invention an
extract derived from the bark of Magnolia officinalis comprising
magnolol as well as honokiol is used in all embodiments of the
invention.
[0094] The term "genistein" as used herein comprises the aglycone
(4',5,7-trihydroxyisoflavone) and derivatives thereof, e.g.,
genistein glycosides, genistein sulfates, genistein
glucuronides.
[0095] Genistein is preferably used in a concentration so that the
daily consumption by an animal including humans (e.g. weighing
about 70 kg) is in the range of from 0.5 mg/day to 2000 mg/day. A
nutraceutical preferably comprises for example 0.2 mg to 500 mg of
genistein per serving. A pharmaceutical composition may for example
comprise a genistein in an amount from 0.5 mg to 500 mg per dosage
unit, e.g., per capsule or tablet, or from 0.5 mg per daily dose to
2000 mg per daily dose of a liquid formulation.
[0096] The term "resveratrol" as used herein comprises a
derivative, metabolite or analogue thereof. The carbon-carbon
double bond may be trans or cis and includes cis/trans mixtures.
Etherified or esterified hydroxy groups may be derived from
unsubstituted or substituted, straight or branched chain alkyl
groups having 1 to 26 carbon atoms or from unsubstituted or
substituted, straight or branched chain aliphatic, araliphatic or
aromatic carboxylic acids having 1 to 26 carbon atoms. Etherified
hydroxy groups may further be glycoside groups and esterified
hydroxy groups may further be glucuronide or sulfate groups. Of
primary interest for the purposes of the invention is
(trans)-resveratrol.
[0097] Resveratrol is preferably used in amount sufficient to
administer to an animal including humans (e.g. weighing about 70
kg) a dosage from 0.5 mg/day to 2000 mg/day, more preferably from 5
mg/day to 500 mg/day. Thus, if the composition is a nutraceutical
composition the amount of a resveratrol comprised therein is
preferably in the range from 0.2 mg to 500 mg per serving. If the
composition is a pharmaceutical composition such composition may
preferably comprise from 0.5 mg to 500 mg per solid dosage unit,
e.g., per capsule or tablet, or from 0.5 mg per daily dose to 2000
mg per daily dose of a liquid formulation.
[0098] The term "EGCG" as used herein comprises
(-)-epigallocatechin gallate (EGCG in the narrower sense) and/or
one or more derivatives (esterified forms, glycosides, sulphates)
thereof, or other catechins found in green tea such as (-)
epigallocatechin (EGC), (-) epicatechin-3-gallate (ECG), (-)
epicatechin (EC), (+) gallocatechin, and (+) catechin and
derivatives thereof. Of primary interest for use in the present
invention is (-)-epigallocatechin gallate.
[0099] EGCG is preferably used in a concentration so that the daily
consumption by an animal including humans (e.g. weighing about 70
kg) is in the range of from 5 mg/day to 2000 mg/day, preferably
from 20 mg/day to 300 mg/day. A nutraceutical composition
preferably comprises from 2 mg to 500 mg of EGCG per serving. If
the composition is a pharmaceutical composition such composition
may comprise EGCG for example in an amount from 5 mg to 500 mg per
dosage unit, for example per capsule or tablet, or from 10 mg per
daily dose to 2000 mg per daily dose of a liquid formulation.
[0100] The term boswellic acid encompasses pure boswellic acid and
derivatives thereof as well as extracts comprising boswellic acid.
Boswellic extract comprising e.g. 3-O-acetyl-11-keto-beta-boswellic
acid, are known to the person skilled in the art. For instance, it
is available on the market in a dietary supplement called
5-LOXIN.RTM. (company PL Thomas). The extract itself it available
as WokVel.RTM. from Geni Herbs. It may be extracted from Boswellia
serrata.
[0101] The daily intake by a human adult (weighing approximately 70
kg) of boswellic acid (extracts) is preferably between 5 and 1000
mg per day, preferably between 100 and 500 mg per day.
[0102] A nutraceutical composition preferably comprises between 5
mg and 500 mg of boswellic acid or boswellic acid extract per
serving. If the composition is a pharmaceutical composition such
composition may preferably comprise boswellic acid or boswellic
acid extract in an amount from 50 mg to 500 mg per dosage unit,
e.g., per capsule or tablet, or from 50 mg per daily dose to 1000
mg per daily dose of a liquid formulation.
[0103] Methylsulfonylmethane (MSM) may be synthesized by methods
known to the person skilled in the art. Daily intake of
methylsulfonylmethane by a human adult (weighing approximately 70
kg) is preferably between 100 and 7000 mg per day, more preferably
between 500 and 2000 mg/day, most preferably between 250 and 750 mg
per day.
[0104] A nutraceutical preferably comprises 5 mg to 3000 mg of MSM
per serving. A pharmaceutical may preferably comprise MSM in an
amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or
tablet, or from 250 mg per daily dose to 750 mg per daily dose of a
liquid formulation.
[0105] Within the framework of the invention SAMe is defined as
S-adenosylmethionine. SAMe is commercially available and is
preferably dosed between 50 and 3000 mg/day. Examples of amounts
used in commercially available products are: 200 mg SAMe (from 400
mg of SAMe-tosylate disulfate); 400 mg S-adenosyl L-methionine
(from SAMe); 200 mg S-adenosyl methionine; 400 mg SAMe (as
S-adenosylmethionine 1,4-butanedisulfonate).
[0106] A nutraceutical preferably comprises 5 mg to 1000 mg of SAMe
per serving. A pharmaceutical may preferably comprise SAMe in an
amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or
tablet, or from 10 mg per daily dose to 3000 mg per daily dose of a
liquid formulation.
[0107] Collagen hydrolysate is a protein mixture which may be
extracted from animal cartilage. It is commercially available from
many supplement companies. Collagen hydrolysate and collagen are
commercially available and the daily intake thereof by a human
adult (weighing approximately 70 kg) is preferably between 500 and
10000 mg per day, preferably between 2000 and 8000 mg per day.
[0108] Unhydrolyzed or undenatured collagen, herein referred to as
`collagen` may be isolated from chicken sternum by methods known to
the person skilled in the art.
[0109] A nutraceutical preferably comprises between 5 mg and 5000
mg of collagen or collagen hydrolysate per serving. A
pharmaceutical composition may preferably comprise collagen in an
amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or
tablet, or from 10 mg per daily dose to 5000 mg per daily dose of a
liquid formulation.
[0110] The term "ascorbyl phosphate" as used herein denotes metal
salts of mono- and poly-phosphoric acid esters of ascorbic acid
wherein the phosphorylated hydroxy group of the ascorbic acid
molecule features one or more phosphoric acid (phosphate) units,
and metal cations, e.g. sodium and/or magnesium or calcium ions,
are also present. The term "poly" generally denotes 2-10,
preferably 2-4, phosphate units. The ascorbyl phosphates may also
be referred to in general as "ascorbyl (poly)phosphates" to embrace
both mono- and polyphosphates. Typical ascorbyl phosphates for use
in the present invention are L-ascorbic acid phosphate ester salts
such as sodium ascorbyl phosphate, potassium ascorbyl phosphate,
magnesium ascorbyl phosphate, calcium ascorbyl phosphate and sodium
magnesium L-ascorbyl-2-monophosphate. Commercially available
ascorbyl phosphates comprise trisodium L-ascorbyl-2-monophosphate
which is available as STAY-CO.RTM.50 from DSM Nutritional Products
AG, (4303 Kaiseraugst, Switzerland) and magnesium L-ascorbyl
phosphate available from Showa Denko) and sodium magnesium
L-ascorbyl-2-monophosphate and L-ascorbic acid-monophosphate which
is available as ROVIMIX.RTM. STAY-C.RTM. 35 from DSM Nutritional
Products AG, (4303 Kaiseraugst, Switzerland). The preferred
ascorbyl phosphate for the purposes of the present invention is
trisodium L-ascorbyl-2-monophosphate. The ascorbyl phosphate may be
incorporated into the nutraceutical, pharmaceutical, cosmetic or
dermatological preparations in many dosage amounts as known to the
person skilled in the art.
[0111] Lycopene (.psi.,.psi. carotene; C.sub.40H.sub.56;
CAS-number: 502-65-8) belongs to the carotenoid family and contains
11 conjugated double-bonds and an additional two non-conjugated
carbon-carbon double-bonds. Lycopene is one of the major dietary
carotenoids and is found in various fruits and vegetables,
especially in tomatoes and tomato products. It also occurs e.g. in
water melon, pink grapefruit, guava.
[0112] Lycopene is preferably used in a concentration so that the
daily consumption by an animal including humans (e.g. weighing
about 70 kg) is in the range of from 0.05 mg/day to 50 mg/day, more
preferably from 0.5 mg/day to 30 mg/day. A nutraceutical
composition preferably comprises 0.05 mg to 50 mg of lycopene per
serving. If the composition is a pharmaceutical composition such
composition may preferably comprise Lycopene in an amount from 0.5
mg to 50 mg per dosage unit, e.g., per capsule or tablet, or a
liquid formulation.
[0113] The chemical structure of cardol diene is given in FIG. 1,
structure (XII). The chemical structure of cardol triene is given
in FIG. 1, structure (XIII)
[0114] Preferably cardol diene (XII) is used in the composition of
the present invention.
[0115] Cardol diene (XII) and/or cardol triene (XIII) is preferably
used in a concentration so that the daily consumption by an animal
including humans (e.g. weighing about 70 kg) is in the range of
from 1 mg/day to 2000 mg/day, preferably from 5 mg/day to 500
mg/day. A nutraceutical composition preferably comprises between
0.2 mg and 1000 mg of cardol diene (XII) and/or cardol triene
(XIII) per serving. In case of a pharmaceutical composition the
amount of cardol diene (XII) and/or cardol triene (XIII) may be
selected from 0.5 mg and 2000 mg per dosage unit, e.g., per capsule
or tablet, or between 1 mg per daily dose and 3000 mg per daily
dose of a liquid formulation.
[0116] Cardol diene (XII) and/or cardol triene (XIII) may also be
used in the form of an extract for instance an--preferably organic
phase or supercritical fluid--extract of the cashew plant
(Anacardium occidentale)) or a part of the cashew plant, for
example in the form of an extract of cashew fruit.
[0117] Cardol diene (XII) and/or cardol triene (XIII) may be
synthesized or extracted and/or purified by methods known to the
person skilled in the art.
[0118] Cardol diene (XII) and/or cardol triene (XIII) are
preferably derived from the cashew plant that may be obtained from
conventional and commercially available sources such as growers. A
number of phenolic compounds are found in Anacardium occidentale,
the cashew nut, the cashew nut shell, the cashew apple, and from
various Toxicodendron species like T. radicans, T diversilobum,
also from Rhus verniciflua, and Melanorrhoea usitata.
[0119] Cardol diene (XII) and/or cardol triene (XIII) as employed
herein may be prepared by a number of methods known in the art. The
mentioned plants may be processed by any suitable means to obtain
the compositions described. For example, cashew apple may be
extracted to obtain a mixture. Cardol diene (XII) and/or cardol
triene (XIII) may be obtained directly from the mixture or the
mixture may be fractionated and/or purified to obtain cardol diene
(XII) and/or cardol triene (XIII). The compositions may be
fractionated and/or purified by a number of methods known to the
person skilled in the art. Examples of fractionating methods
include partitioning with an organic solvent, chromatography, for
example high pressure liquid chromatography (HPLC) or the use of
supercritical fluids.
[0120] Cardol diene (XII) and/or cardol triene (XIII) can for
example be obtained by extraction of dried plant material of
Anacardium occidentale with methanol: methyl tert butyl ether (9:1)
and by subsequent fractionation of the thus obtained crude extract
by preparative HPLC in a buffered solvent system.
[0121] Cashew fruit extract is preferably used in such an amount
that the amount of cardol diene (XII) and/or cardol triene (XIII)
is as described above.
[0122] Hydroxytyrosol and/or oleuropein (I) may also be combined
with Glycyrrhiza foetida. The term `Glycyrrhiza foetida`
encompasses all parts of the plants derived from Glycyrrhiza
foetida as well as extracts derived thereof.
[0123] Hydroxytyrosol and/or oleuropein (I) may also be combined
with compounds isolated from Glycyrrhiza foetida such as
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), Cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), more preferably enriched in at least one compound
from the group of cannabigerolic acid monomethyl ether,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid and
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol.
[0124] Glycyrrhiza foetida as a whole or parts thereof such as the
seedlings, the young plants, the leaves, the flowers (optionally in
dried or ground form) or seeds may be used in dried and grinded
form or may be extracted conventionally with solvents like ethanol,
dichloromethane at reflux temperature or at lower temperature.
Alternatively, it may be extracted with supercritical fluids like
SF carbon dioxide or by steam distillation of the plant with water
followed by sampling of the distilled organic part. Sampling may
for example be done by extraction with an organic solvent like
dichloromethane, ethylacetate etc. Subsequent removal of the
solvent gives the desired Glycyrrhiza foetida extract.
[0125] Optionally, the thus obtained Glycyrrhiza foetida extract
may be subjected to further processing steps to enrich the content
of specific compounds to give an extract of Glycyrrhiza foetida
e.g. enriched in
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfiutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), Cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), more preferably enriched in at least one compound
from the group of cannabigerolic acid monomethyl ether,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid and 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol.
Compounds III to XI are depicted in FIG. 1.
[0126] Glycyrrhiza foetida extracts enriched in at least one
compound selected from the group of cannabigerolic acid monomethyl
ether,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid and 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol
are preferred.
[0127] All compounds (III)-(XI) can e.g. be obtained by extraction
of dried plant material of Glycyrrhiza foetida with methanol:
methyl tert butyl ether (MTB) (9:1) and by subsequent fractionation
of the thus obtained crude extract by preparative HPLC, for example
in a buffered solvent system or can be synthesized. Examples of
fractionating methods include partitioning with an organic solvent,
chromatography, for example high pressure liquid chromatography
(HPLC) or the use of supercritical fluids. Of course the compounds
of (III)-(XI) may also be accessible via chemical synthesis)
[0128] Preferably compounds (III) to (XI) are used in the form of
an extract derived from Glycyrrhiza foetida.
[0129] The Glycyrrhiza foetida extract and/or the compounds
contained therein are preferably derived from Glycyrrhiza foetida
that may be obtained from conventional and commercially available
sources such as growers.
[0130] The Glycyrrhiza foetida as well as the extracts derived
thereof are preferably used so that the daily consumption by an
animal including humans (e.g. weighing about 70 kg) is in the range
of from 0.5 mg/day to 2000 mg/day, preferably from 5 mg/day to 500
mg/day. A nutraceutical composition preferably comprises 0.5 mg to
1000 mg of a Glycyrrhiza foetida extract. If the composition is a
pharmaceutical composition such composition may comprise the
Glycyrrhiza foetida extract in an amount from preferably 1 mg to
2000 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg
per daily dose to 3000 mg per daily dose of a liquid
formulation.
[0131] The individual compounds isolated from the Glycyrrhiza
foetida are preferably used in a concentration so that the daily
consumption by an animal including humans (e.g. weighing about 70
kg) is in the range of from 0.5 mg/day to 2000 mg/day, preferably
from 5 mg/day to 500 mg/day. A nutraceutical composition preferably
comprises 0.5 mg to 1000 mg of such a compound. If the composition
is a pharmaceutical composition such composition may comprise one
or more of the compounds contained in Glycyrrhiza foetida in an
amount from preferably 1 mg to 2000 mg per dosage unit, e.g., per
capsule or tablet, or from 1 mg per daily dose to 3000 mg per daily
dose of a liquid formulation.
[0132] If the individual compounds are used in form of a
Glycyrrhiza foetida extract, the extract is preferably used in such
an amount that the amount of individual compound(s) is as described
above.
[0133] Extracts of Harpagophytum procumbens (Devil's claw) are on
the market. The active ingredient in Devil's Claw is a glycoside
called harpagoside. Other constituents of Devil's Claw include
beta-sitosterol, harpagide, procumbine, sugars, gum resin and
bitter ingredients. Devil's Claw's dosage can easily be determined
by the person skilled in the art and is preferably within the same
range as on the market.
[0134] Milk protein concentrate includes milk protein hydrolysates
and is commercially available for example as MicroLactin.TM. from
Brandenburg nutrition or as Peptopro from DSM Food Specialities.
It's dosage can easily be determined by the person skilled in the
art and is preferably within the same range as on the market.
[0135] Horse chestnut extract refers to an extract obtained from
Aesculus hippocastanum comprising a mixture of saponins.
[0136] Other examples of compounds with which hydroxytyrosol and/or
oleuropein (I) may be combined to get a synergistic effect are
solubilized keratin, celery seed extract, cetylated fatty acids,
carnitine thymoquinone, lutein, zeaxanthin and
.beta.-cryptoxanthin.
[0137] In another aspect, the invention relates to a cosmetic or
dermatological preparation (the latter preparation are a specific
type of a pharmaceutical) comprising an effective amount of the
composition of the invention and a cosmetically or dermatologically
acceptable carrier.
[0138] The cosmetic or dermatological composition may further
comprise conventional cosmetic respectively dermatological
adjuvants and/or additives and/or additional active
ingredients.
[0139] Preferably the cosmetic or dermatological preparations are
skin care formulations for the treatment, co-treatment or
prevention of inflammation of the skin, in particular of sunburn
caused by UV-radiation, of contact dermatitis (particularly diaper
area dermatitis), atopic dermatitis, xerosis, eczema, rosacea,
seborrhea, psoriasis, neurodermitis, thermal burns, photoageing or
for the treatment, co-treatment or prevention of impure skin.
Examples of impure skin include pimples, acne and other skin
impurities with an inflammatory aspect.
[0140] The term "effective amount" means preferably at least 0.001%
of each active agents as listed above based on the total weight of
the cosmetic or dermatological composition. Preferably, the
cosmetic or dermatological preparations comprise the active agents
selected from the list above in an amount between 0.01 wt.-% and 20
wt.-%, more preferably between 0.05 and 10 wt.-%, still more
preferably between 0.1 and 5 wt.-%.
[0141] The amount of the cosmetic or dermatological preparation
which is to be applied to the skin depends on the concentration of
the active ingredients in the preparation and the desired cosmetic
or pharmaceutical effect. For example, the application can be such
that a creme is applied to the skin. A creme is usually applied in
an amount of about 1 to 2 mg creme/cm.sup.2 skin. The amount of the
composition which is applied to the skin is, however, not critical,
and if with a certain amount of applied composition the desired
effect cannot be achieved, a higher concentration of the active
preparations which contain more active ingredient might be
employed.
[0142] The invention also relates to the use of the cosmetic
preparation for the cosmetic treatment, co-treatment or prevention
of inflammation of the skin, in particular for the cosmetic
treatment, co-treatment or prevention of sunburn, contact
dermatitis (particularly diaper area dermatitis), atopic
dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis,
neurodermitis, thermal burns or photoageing.
[0143] Also, the invention relates to a method for the treatment,
co-treatment or prevention of inflammation of the skin, in
particular of sunburn in humans, of impure skin such as for example
acne or of photoageing which is associated with chronic skin
inflammation, said method comprising the step of administering an
effective amount of the dermatological composition according to the
invention to humans, which are in need thereof. Also, the invention
relates to a method for cosmetic treatment, co-treatment or
prevention of inflammation of the skin, in particular of sunburn or
of impure skin by a cosmetic preparation according to the
invention. Sunburn prevention is preferably achieved with topical
application comprising the composition of the invention preferably
in combination with suitable light screening agents.
[0144] The cosmetic or dermatological preparations according to the
invention may be in the form of a suspension or dispersion in
solvents or fatty substances, or alternatively in the form of an
emulsion or micro emulsion (in particular of O/W or W/O type, O/W/0
or W/O/W-type, wherein O stands for oil phase and wherein W stands
for water phase), such as a cream, a paste, a lotion, a thickened
lotion or a milk, a vesicular dispersion in the form of an
ointment, a gel, a solid tube stick or an aerosol mousse, and may
be provided in the form of a mousse, foam or a spray foams, sprays,
sticks or aerosols or wipes. Examples of cosmetic or dermatological
preparations are skin care preparations, in particular, body oils,
body lotions, body gels, treatment creams, skin protection
ointments, moisturizing gels, moisturizing sprays, revitalizing
body sprays, after sun preparations or sunscreen formulations.
[0145] The cosmetic or dermatological composition for the
treatment, co-treatment or prevention of inflammation of the skin,
such as for example sunburn, photoageing or impure skin may be in a
form that is conventional for oral administration, examples of
which are described above and also include beauty foods and
supplements.
[0146] The cosmetic or dermatological preparations of the invention
for instance as sunscreen formulations or after sun preparations
may further comprise the usual cosmetic respectively dermatological
adjuvants and/or additives such as preservatives/antioxidants,
fatty substances/oils, water, organic solvents, silicones,
thickeners, softeners, emulsifiers, additional light screening
agents, antifoaming agents, moisturizers, fragrances, surfactants,
fillers, sequestering agents, anionic, cationic, nonionic or
amphoteric polymers or mixtures thereof, propellants, acidifying or
basifying agents, dyes, colorants, pigments or nanopigments, light
stabilizers, insect repellants, skin tanning agents, skin whitening
agents, antibacterial agents, preservatives active ingredients or
any other ingredients usually formulated into cosmetics.
[0147] Light screening agents which may be incorporated into
cosmetic or dermatological preparations of the invention for
instance sunscreen formulations are advantageously selected from
IR, UV-A, UV-B, UV-C and/or broadband filters. Examples of UV-B or
broad spectrum screening agents, i.e. substances having absorption
maximums between about 290 and 340 nm may be organic or inorganic
compounds. Organic UV-B or broadband screening agents are e.g.
acrylates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate
(octocrylene, PARSOL.RTM. 340), ethyl 2-cyano-3,3-diphenylacrylate
and the like; camphor derivatives such as 4-methyl benzylidene
camphor (PARSOL.RTM. 5000), 3-benzylidene camphor, camphor
benzalkonium methosulfate, polyacrylamidomethyl benzylidene
camphor, sulfo benzylidene camphor, sulphomethyl benzylidene
camphor, therephthalidene dicamphor sulfonic acid and the like;
Cinnamate derivatives such as ethylhexyl methoxycinnamate
(PARSOL.RTM. MCX), ethoxyethyl methoxycinnamate, diethanolamine
methoxycinnamate (PARSOL.RTM. Hydro), isoamyl methoxycinnamate and
the like as well as cinnamic acid derivatives bond to siloxanes;
p-aminobenzoic acid derivatives, such as p-aminobenzoic acid,
2-ethylhexyl p-dimethylaminobenzoate, N-oxypropylenated ethyl
p-aminobenzoate, glyceryl p-aminobenzoate; benzophenones such as
benzophenone-3, benzophenone-4,2,2',4,4'-tetrahydroxy-benzophenone,
2,2'-dihydroxy-4,4'-dimethoxybenzophenone and the like; esters of
benzalmalonic acid such as di-(2-ethylhexyl)
4-methoxybenzalmalonate; esters of 2-(4-ethoxy-anilinomethyl
ene)propandioic acid such as 2-(4-ethoxy anilinomethylene)
propandioic acid diethyl ester as described in the European Patent
Publication EP 0895 776; organosiloxane compounds containing
benzmalonate groups as described in the European Patent
Publications EP 0358584 B1, EP 0538431 B1 and EP 0709080 A1 such as
polysilicone-15 (PARSOL.RTM. SLX); drometrizole trisiloxane
(Mexoryl XL); imidazole derivatives such as e.g. 2-phenyl
benzimidazole sulfonic acid and its salts (PARSOL.RTM.HS). Salts of
2-phenyl benzimidazole sulfonic acid are e.g. alkali salts such as
sodium- or potassium salts, ammonium salts, morpholine salts, salts
of primary, sec. and tert. amines like monoethanol amine salts,
diethanol amine salts and the like; salicylate derivatives such as
isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate,
ethylhexyl salicylate (PARSOL.RTM. EHS, NEO Heliopan OS), isooctyl
salicylate or homomethyl salicylate (homosalate, PARSOL.RTM. HMS,
NEO Heliopan OS) and the like; triazine derivatives such as
ethylhexyl triazone (Uvinul T-150), diethylhexyl butamido triazone
(Uvasorb HEB). Encapsulated UV-filters such as encapsulated
ethylhexyl methoxycinnamate (Eusolex UV-pearls) or microcapsules
loaded with UV-filters as e.g. disclosed in EP 1471995 and the
like. Inorganic compounds are pigments such as microparticulated
TiO.sub.2, ZnO and the like. The term "microparticulated" refers to
a particle size from about 5 nm to about 200 nm, particularly from
about 15 nm to about 100 nm. The TiO.sub.2 particles may also be
coated by metal oxides such as e.g. aluminum or zirconium oxides or
by organic coatings such as e.g. polyols, methicone, aluminum
stearate, alkyl silane. Such coatings are well known in the
art.
[0148] Examples of broad spectrum or UV A screening agents i.e.
substances having absorption maxima between about 320 and 400 nm
may be organic or inorganic compounds e.g. dibenzoylmethane
derivatives such as 4-tert. butyl-4'-methoxydibenzoyl-methane
(PARSOL.RTM. 1789), dimethoxydibenzoylmethane,
isopropyldibenzoylmethane and the like; benzotriazole derivatives
such as
2,2'-methylene-bis-(6-(2H-benzotriazole-2-yl)-4-(1,1,3,3,-tetramethylbuty-
l)-phenol (TINOSORB M) and the like; bis-ethylhexyloxyphenol
methoxyphenyl triazine (Tinosorb S) and the like;
phenylene-1,4-bis-benzimidazolsulfonic acids or salts such as
2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic acid)
(Neoheliopan AP); amino substituted hydroxybenzophenones such as
2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester
(Uvinul A plus) as described in the European Patent Publication EP
1046391; Ionic UV-A filters as described in the International
Patent Publication WO2005080341 A1. Pigments such as
microparticulated ZnO or TiO2 and the like. The term
"microparticulated" refers to a particle size from about 5 nm to
about 200 nm, particularly from about 15 nm to about 100 nm. The
particles may also be coated by other metal oxides such as e.g.
aluminum or zirconium oxides or by organic coatings such as e.g.
polyols, methicone, aluminum stearate, alkyl silane. Such coatings
are well known in the art.
[0149] As dibenzoylmethane derivatives have limited photostability,
it may be desirable to photostabilize these UV-A screening agents.
Thus, the term "conventional UV-A screening agent" also refers to
dibenzoylmethane derivatives such as e.g. PARSOL.RTM. 1789
stabilized by, e.g. 3,3-Diphenylacrylate derivatives as described
in the European Patent Publications EP 0 514 491 B1 and EP 0 780
119 A1; Benzylidene camphor derivatives as described in the U.S.
Pat. No. 5,605,680; Organosiloxanes containing benzmalonate groups
as described in the European Patent Publications EP 0358584 B1, EP
0538431 B1 and EP 0709080 A1.
[0150] Active ingredients which may be included in the cosmetic or
dermatological preparations of the invention are for example
vitamins and derivatives thereof, for example tocopherol,
tocopherol acetate, ascorbic acid, ascorbyl phosphate, vitamin Q,
D, and K, retinol, retinal, retinoic acid, retinol acetate, retinol
palmitate, biotin, carotenoid derivatives such as beta-carotene,
lycopene, astaxanthin, vegetable extracts, antibacterial
ingredients, instable amino acids comprising dipeptides,
oligopeptides and polypeptides such as methionine, cysteine,
cystine, tryptophan, phenylalanine, tyrosine, phenols, polyphenols
or flavanoids, bisabolol, allantoin, phytantriol, panthenol, AHA
acids, ubiquinones such as coenzyme Q 10, ceramides,
pseudoceramides, essential oils, plant extracts deoxyribonucleic
acid, phytanic acid.
[0151] The necessary amounts of the cosmetic and dermatological
adjuvants, additives and/or additional active ingredients can,
based on the desired product, easily be chosen by a person skilled
in the art and will be illustrated in the examples, without being
limited hereto.
[0152] In yet another embodiment, the invention relates to the use
of hydroxytyrosol and/or oleuropein (I) for enhancing the
anti-inflammatory activity of one or several compounds selected
from the group of ligustilide, oleuropein aglycone (II), tyrosol,
extract from the bark of Magnolia officinalis, magnolol, honokiol,
genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen
hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein,
zeaxanthin, .beta.-cryptoxanthin, Devil's Claw, milk protein
concentrate, solubilized keratin, celery seed extract, cetylated
fatty acids, carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract, in
particular of ligustilide, honokiol, genistein, resveratrol and
EGCG.
[0153] Preferably, the invention relates to the use of
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
for enhancing the anti-inflammatory activity of one or several
compounds selected from the group of ligustilide, honokiol,
genistein, resveratrol and EGCG.
[0154] Thus, the invention relates to the use of hydroxytyrosol
and/or oleuropein (I), in particular hydroxytyrosol, for enhancing
the anti-inflammatory activity of ligustilide.
[0155] In another embodiment invention relates to the use of
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
for enhancing the anti-inflammatory activity of honokiol. Most
preferably, honokiol is used in the form of an extract from the
bark of Magnolia officinalis comprising honokiol and magnolol.
[0156] In a further embodiment the invention relates to the use
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
for enhancing the anti-inflammatory activity of genistein.
[0157] In an additional embodiment the invention relates to use of
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
for enhancing the anti-inflammatory activity of resveratrol.
[0158] In an additional embodiment the invention relates to use of
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
for enhancing the anti-inflammatory activity of EGCG.
[0159] In another embodiment the invention relates to a method of
enhancing the efficacy of hydroxytyrosol and/or oleuropein (I)
which comprises adding to a composition containing hydroxytyrosol
and/or oleuropein (I) an effective amount of one or several
components selected from the group of ligustilide, oleuropein
aglycone (II), tyrosol, extract from the bark of Magnolia
officinalis, magnolol, honokiol, genistein, resveratrol, EGCG
methylsulfonylmethane, SAMe, collagen hydrolysate, collagen,
ascorbyl phosphate, lycopene, lutein, zeaxanthin,
.beta.-cryptoxanthin, Devil's Claw, milk protein concentrate,
solubilized keratin, celery seed extract, cetylated fatty acids,
carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract, in
particular of ligustilide, honokiol, genistein, resveratrol and
EGCG. The term `an effective amount` refers to an amount necessary
to obtain a synergistic effect. The dosage may, of course, vary
depending upon known factors, such as the physiological
characteristics of the particular composition and its mode and
route of administration; the age, health and weight of the
recipient; the nature and extent of the symptoms; the kind of
concurrent treatment; the frequency of treatment; and the effect
desired and can be adjusted by a person skilled in the art.
[0160] Thus, in a preferred embodiment the invention relates to a
method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I) which comprises adding to a composition containing
hydroxytyrosol and/or oleuropein (I) an effective amount of
ligustilide.
[0161] In another preferred embodiment the invention also relates
to a method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I) which comprises adding to a composition containing
hydroxytyrosol and/or oleuropein (I), in particular hydroxytyrosol,
an effective amount of honokiol. Most preferably, honokiol is used
in the form of an extract from the bark of Magnolia officinalis
comprising honokiol and magnolol.
[0162] In a further preferred embodiment the invention relates to a
method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I), in particular hydroxytyrosol, which comprises
adding to a composition containing hydroxytyrosol and/or oleuropein
(I) an effective amount of genistein.
[0163] In an additional preferred embodiment the invention relates
to a method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I), in particular hydroxytyrosol, which comprises
adding to a composition containing hydroxytyrosol and/or oleuropein
(I) an effective amount of resveratrol.
[0164] In an additional preferred embodiment the invention relates
to a method of enhancing the efficacy of hydroxytyrosol and/or
oleuropein (I), in particular hydroxytyrosol which comprises adding
to a composition containing hydroxytyrosol and/or oleuropein (I) an
effective amount of EGCG.
[0165] It has been found that the compositions according to the
invention are also suitable for the treatment, co-treatment or
prevention of cartilage degradation or cartilage damage in joints
and as such for treatment of the cartilage degradation component of
joint disorders, for example degenerative joints disorders such as
osteoarthritis; or sport injuries. Cartilage degradation is defined
within the framework of the invention as a metabolic disorder of
joint cartilage characterized by increased production of
cartilage-degrading enzymes such as matrix metalloproteases.
[0166] Osteoarthritis is a chronic degenerative disease of the
joint of non-inflammatory origin, which develops by wear and tear
of the joints during aging and results in pain and diminished joint
function. Symptoms of osteoarthritis include pain, stiffness and
loss of mobility in one or more joints. Excessive joint loading
increases the risk of osteoarthritis, hence osteoarthritis mostly
affects the weight-bearing joints such as spine, knees and hips,
but thumb and finger joints may also be affected. Joint disorders
can also results from injury, i.e. microdamage or blunt trauma,
fractures, damage to tendons, menisci or ligaments or can be the
result of excessive mechanical stress or other biomechanical
instability resulting from for example an injury or obesity.
[0167] Joint disorders due to cartilage degradation are leading
causes of disability and dysfunction in the elderly; almost 80% of
people over age 60 show some evidence of these disorders. Age,
genetic factors, muscle disuse and weakness, trauma, obesity and
anatomical abnormalities contribute to the development of the
disorder.
[0168] Joint disorders are difficult to treat. Up till now,
treatment was largely limited to addressing the symptoms mainly
with non-steroidal anti-inflammatory drugs. The drugs are given to
control the pain and to restrain swelling, but do not prevent or
treat damage to the cartilage. The patients experiencing severe
cartilage damage frequently require surgery, including joint
replacement surgery. Therefore, there was a great need for agents
that treat or prevent cartilage loss and damage, which need has
been solved by the present invention.
[0169] The composition of the present invention may have one or
more of the following properties: it maintains and/or improves
joint health, it prevents joint stiffness, it promotes joint
mobility, it provides supple and/or flexible joints, it lubricates
the joints, it relieves arthritis pain, it lessens joint problems,
it provides joint care, it treats or prevents joint degradation, it
provides joint integrity, it retards or prevents the progression of
joint damage, it supports joint function, it promotes joint health
and function, it naturally supports joint health and mobility for
active individuals, it maintains the active flexibility of joints,
it promotes joint flexibility and promotes joint mobility.
[0170] Thus, further objects of the present invention are: [0171]
Use of a composition according to the invention as
cartilage-regenerating and maintaining agent. [0172] Use of a
composition according to the invention for maintenance of joint
health. [0173] Use of a composition according to the invention (for
the manufacture of a composition) for the maintenance and
regeneration of articular cartilage. [0174] A method for the
regeneration and/or maintenance of (articular) cartilage in a
mammal which comprises administering to a mammal in need of such
regeneration and/or maintenance an effective amount of a
composition according to the invention.
[0175] The invention will now be elucidated by way of the following
examples, without however being limited thereto.
EXAMPLES
[0176] In the following examples, "Group (A)" is defined as the
following group of compounds: ligustilide, oleuropein aglycone
(II), tyrosol, extract from the bark of Magnolia officinalis,
magnolol, honokiol, genistein, resveratrol, EGCG
methylsulfonylmethane, SAMe, collagen hydrolysate, collagen,
ascorbyl phosphate, lycopene, lutein, zeaxanthin,
.beta.-cryptoxanthin, Devil's Claw, milk protein concentrate,
solubilized keratin, celery seed extract, cetylated fatty acids,
carnitine, thymoquinone,
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V),
2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid
(VI), cannabigerolic acid monomethyl ether (VII),
2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic
acid (VIII),
3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the
compound of formula (X) and
2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-be-
nzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew
fruit extract, boswellic acid, carnosic acid, ursolic acid, horse
chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and
derivatives, Glycyrrhiza foetida and white willow bark extract.
[0177] Hydroxytyrosol is commercially available from Cayman
Chemicals or was synthesized by DSM Nutritional Products.
Resveratrol, ligustilide, EGCG and genistein was synthesized by DSM
Nutritional Products. Magnolia Bark extract was from Novanat
Bioresources Co. Ltd. China and contained according to the
specification >80% Magnolol and Honokiol. Oleuropein, Magnolol
and Honokiol may be purchased at Wako Pure Chemical Industries,
Ltd., Japan, Apin Chemicals Ltd, UK, Sigma, or ChromaDex or were
synthesized by DSM Nutritional Products.
Example 1
Synergistic Effect
[0178] The anti-inflammatory effects combinations of OH-tyrosol or
oleuropein and representatives of other groups of natural
substances (isoflavones, catechins, phtalides, hydroxylated
biphenyls) were evaluated in activated macrophages by determining
the inhibition of the synthesis of nitric oxide and/or
pro-inflammatory prostaglandins (PG). PGE.sub.2 plays a critical
role in the inflammation process, while nitric oxide (NO) is a
hallmark of inflammation in various chronic inflammatory diseases
including various forms of arthritis, gastro-intestinal diseases
and metabolic syndrome. The compounds used in the experiment were
dissolved in DMSO in concentrated form and did not contain
byproducts that interfered with the assays. Final vehicle (DMSO)
concentration did not exceed 0.2% v/v in the assays.
[0179] The anti inflammatory effect of compounds was tested in
cellular assays using a murine macrophage indicator cell line,
RAW267.7, which was purchased from American Type Culture
Collection, (ATCC) and cultured in DMEM according to the protocol
provided by ATCC. Cells (.about.50'000/well) were seeded into
flat-bottomed microtiter plates and cultured for one day. Cells
were then starved in complete medium containing 0.25% FCS (D-025).
After overnight culture, medium was removed and replaced by 100
.mu.L of D-025 containing the test compounds at twice the final
concentration. Subsequently, 100 .mu.L of D-025 containing 2
.mu.g/ml LPS was added (i.e. final LPS concentration of 1 .mu.g/ml)
and the cells cultured for 24 hours. Substances were usually tested
in a concentration range from 0.2 to 50 .mu.M (or .mu.g/ml in the
case of extracts) in two-fold dilution steps. Concentrations of
nitrite which was generated from nitric oxide released by cells
were determined by the Griess reaction using sodium nitrite as
standard (see e.g Imai et al. Biochem Biophys Res Comm, 197, 105
[1993]). Briefly, 50 .mu.l of supernatant was mixed with Griess
reagent 1 (25 .mu.L) and Griess reagent 2 (25 .mu.L), centrifuged
and the optical density at 540 nm determined. PGE.sub.2 secreted
into the cell culture medium was determined by EIA obtained from
Cayman Chemicals (Ann Harbor, Wis., USA) and used according to the
manufacturer's instructions. IC.sub.50 values were calculated using
a two-parametric least-square fitting equation
[y=A+((B-A)/(1+((C-x) D))] for best-fit curves (Excel fit software
program).
[0180] In Table 1 it is shown that individually, all substances
inhibited the production of inflammatory mediators. This is
indicated by IC.sub.50 values, which vary between substances
reflecting substance-specific biological potencies.
[0181] In Table 2 it is shown that hydroxytyrosol (OH-Tyrosol) or
oleuropein when combined with resveratrol, ligustilide, EGCG,
honokiol, genistein or Magnolia Bark extract synergistically
inhibits nitric oxide production. A positive value for .DELTA.
(observed-additive) means that the two substances out-perform the
inhibitory power of the two individual components of the mixture.
With `observed` is meant the actual observed inhibition. With
`additive` is meant the theoretical sum of the inhibition of the
two compounds
TABLE-US-00001 TABLE 1 IC.sub.50 values for single substances
Substance IC.sub.50 PGE.sub.2 IC.sub.50 Nitric Oxide OH-Tyrosol 24
.+-. 3 .mu.mol/L 28 .+-. 2 .mu.mol/L Oleuropein 60 .+-. 10
.mu.mol/L 52 .+-. 5 .mu.mol/L Resveratrol 24 .+-. 2 .mu.mol/L 31
.+-. 2 .mu.mol/L EGCG 35 .+-. 3 .mu.mol/L 33 .+-. 2 .mu.mol/L
Ligustilide 10 .+-. 2 .mu.mol/L 15 .+-. 1 .mu.mol/L Genistein 4.6
.+-. 0.6 .mu.mol/L 37 .+-. 2 .mu.mol/L Magnolia Bark 1.2 .+-. 0.4
.mu.g/mL 3.6 .+-. 0.5 .mu.g/mL Honokiol 1.0 .+-. 0.2 .mu.mol/L 8
.+-. 1 .mu.mol/L
TABLE-US-00002 TABLE 2 Synergistic effects on production of nitric
oxide % inhibition of NO Substance Concentration production *
OH-Tyrosol (OT) 12.5 .mu.mol/L 33 Resveratrol (RES) 12.5 .mu.mol/L
19 OT + RES 12.5 .mu.mol/L + 12.5 .mu.mol/L 99 47 OH-Tyrosol (OT)
12.5 .mu.mol/L 33 Ligustilide (LIG) 12.5 .mu.mol/L 38 OT + LIG 12.5
.mu.mol/L + 12.5 .mu.mol/L 99 28 OH-Tyrosol (OT) 12.5 .mu.mol/L 33
EGCG 12.5 .mu.mol/L 12 OT + EGCG 12.5 .mu.mol/L + 12.5 .mu.mol/L 51
6 OH-Tyrosol (OT) 12.5 .mu.mol/L -2 Honokiol (HO) 12.5 .mu.mol/L 66
OT + HO 12.5 .mu.mol/L + 12.5 .mu.mol/L 78 14 OH-Tyrosol (OT) 6.25
.mu.mol/L 7 Genistein (GEN) 25 .mu.mol/L 40 OT + GEN 6.25 .mu.mol/L
+ 25 .mu.mol/L 54 7 OH-Tyrosol (OT) 12.5 .mu.mol/L 16 Magnolia Bark
(MB) 0.25 .mu.g/mL -4 MB + OT 12.5 .mu.mol/L + 0.25 .mu.mg/L 23 11
Oleuropein (OLE) 12.5 .mu.mol/L 8 Resveratrol (RES) 12.5 .mu.mol/L
3 OLE + RES 12.5 .mu.mol/L + 12.5 .mu.mol/L 39 28 Oleuropein (OLE)
3.125 .mu.mol/L 2 Ligustilide (LIG) 3.125 .mu.mol/L 28 OLE + LIG
3.125 .mu.mol/L + 3.125 .mu.mol/L 53 23 *(observed - additive;
Additive = .SIGMA. (compound A (e.g. OT/OLE) + compound B (e.g.
RES/LIG etc)
Example 2
Synergistic Effects Observed with a Combination of Lycopene
Resveratrol and OH-tyrosol
[0182] In a methodological approach that was similar to that
described for Example 1, the synergistic effect of lycopene,
resveratrol and OH-tyrosol was tested on the inflammatory response.
Dose-dependent effects of each substance on the production of
nitric oxide or PGE.sub.2 in macrophages were determined. Unlike
resveratrol or OH-tyrosol, lycopene had no anti-inflammatory effect
(at <8 .mu.mol/L). In the concentration range where synergistic
effects were revealed, single compounds had low or no inhibitory
effect on the production of inflammatory mediators. Yet,
unexpectedly the combination significantly reduced NO produced by
activated macrophages. Similar features were observed with regard
to the effect on PGE.sub.2 production.
TABLE-US-00003 TABLE 3 Synergistic effects on production of nitric
oxide % inhibition of NO IC.sub.50 of pure Substance Concentration
production * compound Lycopene (Ly) 0.5 .mu.mol/L 4 -- >8
.mu.mol/L Resveratrol (Res) 3.13 .mu.mol/L -2 -- 19.3 .mu.mol/L
OH-- tyrosol (OT) 3.13 .mu.mol/L -4 -- 24.1 .mu.mol/L Ly + Res + OT
(0.5 + 3.13 + 17 15 Not applicable 3.13) .mu.mol/L *observed -
additive; Additive = .SIGMA. (Ly + Res + OT)
TABLE-US-00004 TABLE 3 Synergistic effects on PGE.sub.2 production
% inhibition of PGE.sub.2 IC.sub.50 of pure Substance Concentration
production * compound Lycopene (Ly) 0.25 .mu.mol/L -5 -- >8
.mu.mol/L Resveratrol (Res) + 1.56 .mu.mol/L + 23 -- 23.4 .mu.mol/L
OH-- tyrosol (OT) 1.56 .mu.mol/L -- 22.7 .mu.mol/L Ly + Res + OT
(0.25 + 1.56 + 49 26 Not applicable 1.56) .mu.mol/L *observed -
additive; Additive = .SIGMA. (Ly + Res + OT)
[0183] The data surprisingly showed that a combination of lycopene
to resveratrol to OH-tyrosol at a molar ratio of about 1:6:6 exert
a synergistic inhibitory effects on production of inflammatory
mediators as exemplified for nitric oxide and PGE.sub.2.
Example 3
Soft Gelatin Capsule
[0184] Soft gelatin capsules are prepared by conventional
procedures providing a dose of hydroxytyrosol and/or oleuropein (I)
of 200 mg and at least one compound selected from the group of
Group (A) as defined above of 50 mg (e.g. EGCG). A suitable daily
dose is 1 to 8 capsules.
[0185] Other ingredients: glycerol. Water, gelatine, vegetable
oil
Example 4
Hard Gelatin Capsule
[0186] Hard gelatin capsules are prepared by conventional
procedures providing a dose of hydroxytyrosol and/or oleuropein (I)
of 400 mg and at least one component selected from the group of
Group (A) as defined above of 100 mg (e.g. magnolia bark extract).
A suitable daily dose is 1 to 5 capsules.
[0187] Other ingredients:
[0188] Fillers: lactose or cellulose or cellulose derivatives
q.s.
[0189] Lubricant: magnesium stearate if necessary (0.5%)
Example 5
Tablet
[0190] Tablets are prepared by conventional procedures providing as
active ingredient 100 mg of hydroxytyrosol and/or oleuropein (I)
per tablet and at least one component selected from the group of
Group (A) as defined above of 100 mg Ligustilide, and as excipients
microcrystalline cellulose, silicone dioxide (SiO.sub.2), magnesium
stearate, crospovidone NF (which is a disintegration agent) ad 500
mg.
Example 6
Soft Drink
[0191] An orange juice drink coloured with beta-Carotene 10% CWS
and with hydroxytyrosol and at least one component selected from
the group of Group (A) as defined above may be prepared as
follows:
TABLE-US-00005 Ingredients [g] Sugar syrup 64.degree. Brix 156.2
Sodium benzoate 0.2 Ascorbic acid, fine powder 0.2 Citric acid 50%
w/w 5.0 Pectin solution 2% w/w 10.0 hydroxytyrosol 0.5 compound
selected from the group of Group (A) as defined above 0.3 Juice
compound* 30.0 Water to 250.0
[0192] Preparation [0193] Dissolve sodium benzoate in water whilst
stirring [0194] Continue stirring and add sugar syrup, ascorbic
acid, citric acid, pectin solution, juice compound, one after the
other. Do not use a high speed mixer [0195] Dilute the bottling
syrup with (carbonated) water to one liter of beverage
TABLE-US-00006 [0195] *Ingredients Juice compound [g] Orange juice
concentrate 65.degree. Brix 483.3 Lemon Juice Concentrate
45.degree. Brix 173.3 Oily orange flavour 5.0 beta-Carotene 10% CWS
as 10% stock solution 10.0 Deionized water 328.4
[0196] Preparation of Juice Compound [0197] Add the deionized water
to the juice concentrates, stir gently and allow the juice
concentrates to hydrate. [0198] Add the oily flavour and
beta-Carotene 10% CWS stock solution and pre-emulsify in a
rotor-stator-homogenizer. [0199] Homogenize in a high pressure
homogenizer at 200 bar.
Example 7
Preparation of a Dermatological Composition Comprising
Hydroxytyrosol (Treatment Cream) which May be Used for (Cosmetic)
Treatment of Inflammation of the Skin Caused by Sunburn
[0200] A treatment cream may be prepared with the following
ingredients, in the following amounts:
TABLE-US-00007 Ingredients/INCI Nomenclature wt. % A Glyceryl
Myristate 2.00 Hydroxytyrosol 0.20 Compound selected from the group
of Group (A) as 0.01 defined above Cetyl Alcohol 0.50
Caprylic/Capric Triglyceride 5.00 Diisopropyl Adipate 5.00
Tocopheryl Acetate 2.00 BHT 0.05 Phenoxyethanol & Methylparaben
& Ethylparaben & 0.60 Propylparaben & Butylparaben
Disodium EDTA 0.10 Potassium Cetyl Phosphate 2.00 B Aqua (deionized
water) ad 100 Propylene Glycol 2.00 Panthenol 2.00 Ethanol 5.00
Allantoin 0.20 Carbomer 0.30 C Potassium Hydroxide 1.50 D Perfume
q.s. Procedure: Heat part A) and B) to 85.degree. C. while
stirring. When homogeneous, add part B) to A) under agitation. Cool
to about 45.degree. C. while stirring. Add part C). Homogenize at
11000 rpm to achieve a small particle size. Cool to ambient
temperature while stirring. Then add part D).
Example 8
O/W Sun Milk
TABLE-US-00008 [0201] Ingredients/INCI Nomenclature wt. % A)
Dimethico DiethylbenzalmalonatePolysilicone-15 6.00 Neo Heliopan AP
3.00 Hydrogenated Cocoglycerides 3.00 Cetearyl Alcohol 2.00
Caprylic/capric Triglyceride 6.00 Mineral oil 2.00 Tocopheryl
Acetate 1.00 Isostearyl Alcohol 4.00 B) Disodium EDTA 0.10
Phenoxyethanol & Methylparaben & Ethylparaben & 0.60
Propylparaben & Butylparaben Potassium Cetyl Phosphate 2.00
Aqua (e.g. deionized water) ad 100 Propylene Glycol 5.00 Carbomer
0.30 Methylene Bis-Benzotriazolyl Tetramethylbutylphenol 6.00
Potassium Hydroxyde 2.10 C) HIDROX .RTM. 6% freeze dried powder
0.20 Compound selected from the group of Group (A) as 0.05 defined
above Procedure: Heat part A) and B) to 85.degree. C. while
stirring. When homogeneous, add part B) to A) under agitation. Cool
to ambient temperature while stirring and add part C). Homogenize
to achieve a small particle size.
Example 9
Sun Milk Waterproofed
TABLE-US-00009 [0202] Ingredients/INCI Nomenclature wt. % A)
Polysilicone-15Dimethico Diethylbenzalmalonate 6.00 Butyl
Methoxydibenzoylmethane 2.00 4-Methylbenzylidene Camphor 4.00
Ethylhexyltriazone 2.00 Dimethicone 1.00 Cetearyl Alcohol 2.00
Hydrogenated Coco-Glycerides 3.00 C12-15 Alkyl Benzoate 6.00
Dibutyl Adipate 7.00 Tocopheryl Acetate 2.00 BHT 0.05 Disodium EDTA
0.10 Phenoxyethanol & Methylparaben & Ethylparaben &
0.60 Propylparaben & Butylparaben Cetyl Phosphate DEA 2.00 B)
Aqua (e.g. deionized water) ad 100 Propylene Glycol 5.00 Carbomer
0.30 Potassium Hydroxide 1.50 C) Hydroxytyrosol 0.05 Compound
selected from the group of Group (A) as 0.10 defined above
Procedure: Heat part A) and B) to 85.degree. C. while stirring.
When homogeneous, add part B) to A) under agitation. Cool to
ambient temperature while stirring and add part C). Homogenize to
achieve a small particle size.
Example 10
Sun Milk for Babies and Children
TABLE-US-00010 [0203] Ingredients/INCI Nomenclature wt. % A) C12-15
Alkyl Benzoate 5.00 Stearyl Dimethicone 2.00 Cetyl Alcohol 1.00 BHT
0.05 Glyceryl Myristate 4.00 Disodium EDTA 0.10 Phenoxyethanol
& Methylparaben & Ethylparaben & 0.60 Propylparaben
& Butylparaben Cetyl Phosphate 2.00 B) Aqua (e.g. deionized
water) ad 100 Carbomer 0.6 Glycerine 3.00 Potassium Hydroxide 2.4
C) Hydroxytyrosol 0.10 Compound selected from the group of Group
(A) as 0.01 defined above Procedure: Heat part A) and B) to
85.degree. C. while stirring. When homogeneous, add part B) to A)
under agitation. Cool to ambient temperature while stirring and add
part C). Homogenize to achieve a small particle size.
Example 11
Anti Pimple Skin-Tonic
TABLE-US-00011 [0204] Ingredients/INCI Nomenclature wt. % A)
Alkohol 15.00 Glycerin 3.00 Aqua (e.g. deionized water) Ad 100
Disodium EDTA 0.10 HIDROX .RTM. 6% freeze dried powder 1.00
Compound selected from the group of Group (A) as 0.05 defined above
Procedure: Add all ingredients of part 1 and mix intensively until
a homogeneous solution is obtained. Adjust the pH to 6.5 with
acetic acid.
Example 12
Anti-Acne Treatment with Stay-C 50
TABLE-US-00012 [0205] Ingredients/INCI Nomenclature wt. % A)
Glyceryl Myristate 1.50 Cetyl Alcohol 1.50 C12-15 Alkyl Benzoate
4.00 Phenoxyethanol & Methylparaben & Ethylparaben &
0.80 Butylparaben & Propylparaben & Isobutylparaben
Isononyl Isononanoate 2.00 Steareth-2 1.50 Steareth-21 1.50 2
Butylene Glycol 2.00 Glycerin 3.00 Disodium EDTA 0.10 Xanthan Gum
0.30 Arcylates/C10-30 Alkyl Acrylate Crosspolymer 0.25
Hydroxytyrosol 1.00 Aqua (e.g. deionized water) Ad 100 3 Aqua (e.g.
deionized water) 10.00 Sodium Ascorbyl Phosphate 3.00 Sodium
Metabisulfite 0.05 Procedure: Heat part 1 up to 85.degree. C.; and
heat also part 2 up to 85.degree. C. When both have the same
temperature add part 2 to part 1 while homogenizing intensively.
Cool down the product to 35.degree. C. while stirring. Now add part
3 and homogenize intensively again. It is generally recommended to
use vacuum while producing the emulsion.
Example 13
Protective Day Cream
TABLE-US-00013 [0206] Ingredients/INCI Nomenclature wt. % A)
Polysilicone-15Dimethico Diethylbenzalmalonate 4.00 Butyl
Methoxydibenzoylmethane 1.50 Glyceryl Myristate 2.00 Cetyl Alcohol
0.50 Caprylic/Capric Triglyceride 5.00 Diisopropyl Adipate 5.00
Tocopheryl Acetate 2.00 BHT 0.05 Phenoxyethanol & Methylparaben
& Ethylparaben & 0.60 Propylparaben & Butylparaben
Disodium EDTA 0.10 Potassium Cetyl Phosphate 2.00 B) Aqua (e.g.
deionized water) ad 100 Propylene Glycol 2.00 Panthenol 2.00
Ethanol 5.00 Allantoin 0.20 Carbomer 0.30 Potassium Hydroxide 1.50
C) Aqua(e.g. deionized water) 10.00 Sodium Ascorbyl Phosphate 0.50
D) HIDROX .RTM. 2% spray dried powder 0.50 Compound selected from
the group of Group (A) as 0.2 defined above E) Perfume q.s.
Procedure: Heat part A), B) and C) to 85.degree. C. while stirring.
When homogeneous, add part B) and C) to A) under agitation. Cool to
ambient temperature while stirring and add part D) and E).
Homogenize to achieve a small particle size.
Example 14
Dry Dog Feed Comprising Hydroxytyrosol and Genistein
[0207] Commercial dry dog food (Hill's Science diet "Canine
Maintenance dry" for dogs as supplied by Hill's Pet Nutrition GmbH,
Liebigstrasse 2-20, D-22113) is sprayed with an aqueous solution of
hydroxytyrosol and genistein in an amount sufficient to administer
to a subject a daily dose of 200 mg to 1 g hydroxytyrosol and 0.1
mg to 3 mg genistein per kg body weight. Further Vitamin C and E
and beta-carotene are incorporated in an amount sufficient to
provide 30 mg vitamin C/kg, and 300 IU vitamin E/kg and 280 mg
beta-carotene/kg in the final food composition before extruding the
entire blend. The food composition is dried to contain dry matter
of about 90% by weight.
Example 15
Wet Cat Food Comprising Hydroxytyrosol and Genistein
[0208] Commercial wet cat food (Hill's Science diet "Feline
Maintenance wet" for cats as supplied by Hill's Pet Nutrition GmbH,
Liebigstrasse 2-20, D-22113) is mixed with HIDROX.RTM. 2% spray
dried powder in an amount sufficient to administer to a subject a
daily dose of 200 mg to 1 g hydroxytyrosol. Further ROVIMIX.RTM.
STAY-C.RTM. 35 available from DSM Nutritional Products AG, Vitamin
E and beta-carotene are incorporated in an amount sufficient to
provide 30 mg ROVIMIX.RTM. STAY-C.RTM. 35/kg, and 300 IU vitamin
E/kg and 280 mg beta-carotene/kg in the final food composition
before cooking the entire blend. The food composition is dried to
contain a dry matter of about 90% by weight.
Example 16
Cereal Bar/Non Baked
TABLE-US-00014 [0209] Ingredients Quantity [g] Sugar 138.0 Water
54.0 Salt 1.5 Glucose syrup DE38, 43.degree. Be 130.0 Invert sugar
syrup (74-76%) 95.0 Sorbitol syrup 35.0 Palmkernel fat 60.0
Biscofin N 40.0 Lecithin 1.5 Monomuls 90-35-5 (emulsifer) 2.5 Apple
dried and cut 63.0 Raisins 27.0 Cornflakes 100.0 Rice crispies
140.0 Mini Crispini, Wheat 90.0 Hazelnut, roasted 54.0 Skim milk
powder 45.0 Apple flavour 74863-33 2.0 Citric acid* 5.0 HIDROX
.RTM. 2% spray dried powder 1.85 Genistein TG 0.34 Magnolia bark
extract 0.28 .beta.-Carotene 10% B 0.77 Yield 1000.0 *used to
support the apple flavour
[0210] 2. Preparation:
TABLE-US-00015 2.1 Premix HIDROX, Genistein TG, magnolia bark
extract and .beta.-Carotene 10% B with skim milk powder and place
in a Kenwood type mixer 2.2 Add cornflakes, ricecrispies and gently
mix with 2.1. Then add the more humid ingredients as dried apples
and raisins. All ingredients are gently mixed in order to ensure a
good distribution of the dry ingredients 2.3 The following
ingredients are weight into a separate bowl each Sugar, water, salt
Glucose- inverte and sorbitol syrup Biscofin N, Palmkernel fat,
Lecithin and Emulsifier 2.3 Mixture of sugar, water and salt is
heated to 110.degree. C. 2.4 Mixture of the different syrups is
heated to 113.degree. C. and cooled in a cold water bath in order
to stop the cooking process 2.5 Solution 2.3 and 2.4 are combined
2.6 Mixture of Biscofin N, palm kernel fat, lecithin and emulsifier
are molten in a water bath at 75.degree. C. 2.7 Mixture (2.6) of
fats is added to the combined sugar solution (2.5). The later
should be still hot 2.8 Flavour and citric acid is added to the
liquid mass (2.7) 2.9 The liquid mass is added to the dry
ingredients (2.2) in the Kenwood mixer and mixed well with the dry
ingredients 2.10 The mass is put on a marmor plate and rolled to
the desired thickness. Then the mass is cooled down at room
temperature 2.11 Cut into pieces of e.g. one serving size and pack
into e.g. aluminium bags
* * * * *